US6891039B2 - Imidazo [4,5-B] pyridine compounds and their pharmaceuticals use - Google Patents

Imidazo [4,5-B] pyridine compounds and their pharmaceuticals use Download PDF

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US6891039B2
US6891039B2 US10/601,690 US60169003A US6891039B2 US 6891039 B2 US6891039 B2 US 6891039B2 US 60169003 A US60169003 A US 60169003A US 6891039 B2 US6891039 B2 US 6891039B2
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alkyl
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substituted
fluorophenyl
pyridine
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Lászlo Révész
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to heterocyclic compounds, in particular to thiazoles and imidazopyridines and to their use for treating TNF ⁇ and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
  • Nu is a heterocyclic nucleus selected from a thiazole in which the R 1 , R 2 and R 3 substituents are disposed as indicated below and an imidazo[4,5-b]pyridine in which the R 1 , R 2 and R 3 substituents are disposed as indicated below
  • halo or halogen denote I, Br, Cl or F.
  • C 3 -C 18 heteroaryl, C 4 -C 19 heteroaralkyl and C 3 -C 18 heterocycloalkyl denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom e.g. N, O or S, and which in the case of C 4 -C 19 heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.
  • R 3 ′ is aryl, it is preferably heteroaryl, e.g. pyridyl (e.g. 4-pyridyl) or pyrazyl, each optionally substituted, e.g. by 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • heteroaryl e.g. pyridyl (e.g. 4-pyridyl) or pyrazyl, each optionally substituted, e.g. by 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • R 3 ′ is cycloalkyl it is preferably C 3 -C 8 , especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • C 3 -C 8 especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • R 3 ′ is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • R 4 ′ When R 4 ′ is aryl it is preferably phenyl. When R′ 4 is cycloalkyl, it is preferably C 3 -C 7 cycloalkyl e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R′ 4 may be unsubstituted or substituted, conveniently mono-substituted, e.g.
  • phenyl conveniently meta or para substituted, by halogen, C 1 -C 4 alkyl, halo-substituedC 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy or optionally mono- or di-C 1 -C 4 alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
  • Y is C 1 -C 4 alkylene, it is preferably C 1 -C 2 alkylene, and is optionally substituted, e.g. by C 1 -C 4 alkyl (e.g. methyl), halogen, hydroxy, C 1 -C 4 alkoxy, or amino.
  • C 1 -C 4 alkyl e.g. methyl
  • halogen hydroxy, C 1 -C 4 alkoxy, or amino.
  • R′ 2 is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF 3 , 3-Cl, or 3,4-difluoro substituted phenyl.
  • halogen or a halogen-containing group e.g. 4-fluorophen-1-yl, or 3-CF 3 , 3-Cl, or 3,4-difluoro substituted phenyl.
  • R′ 3 is H, C 1 -C 6 alkyl, phenyl, pyridyl, morpholinyl, piperidyl, piperazyl, or optionally mono- or di-C 1-4 alkyl substituted amino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • X is —NH—Y′—, —O— or —S—, where Y′ is —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )— or a direct bond
  • the invention provides a compound of formula II′
  • R 4 ′′ is unsubstituted or monosubstituted by halogen, C 1 -C 4 alkyl (e.g. methyl), C 1 -C 4 alkoxy (e.g. methoxy), hydroxy or CF 3.
  • R 10 is halogen, e.g. F.
  • X′′ is —NH—Y′ where Y′ is —CH(CH 3 )—.
  • the Invention includes the following compounds:
  • novel thiazoles of the invention in particular the compounds of formulae II and II′ and the specific compounds listed above are hereinafter referred to “Agents of the Invention”.
  • Agents of the Invention of formula II′′ wherein R 3 ′′, R 5 ′′, R 10 and Z are as previously defined and X′′′ is —NH— may be prepared by reacting the corresponding precursor compound of formula III ml or III′ wherein R 3 ′′ and R 10 are as previously defined, with the corresponding R 4 ′′—NH 2 derivative.
  • the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane. Thereafter, if desired, the compound of Formula II′′ obtained may be converted into a further compound of Formula II′′ or otherwise treated as required.
  • the precursor compound of formula III may be prepared by controlled oxidation of the corresponding 5(2-methylthio-4-pyrimidinyl)-4-phenythiazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride.
  • the corresponding 5(-4-pyrimidinyl/pyridinyl)-4-phenylthiazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula IV or IV′ wherein R 10 is as defined above, with a corresponding thioamide of formula R 3 ′C(S)NH 2 , typically at elevated temperature.
  • the compounds of formula IV and IV′ may be prepared by bromination of the corresponding acetophenone, e.g. 2-(2-methylthio-4-pyrimidinyl)acetophenone.
  • the acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N-methylbenzamide with the corresponding pyrimidine, e.g. 4methyl-2-(methylthio) pyrimidine, for instance in a THF containing organic solvent with cooling.
  • the invention includes a process for the preparation of a compound of formula II′′ wherein R 3 ′′, R 4 ′′, R 10 and Z are as previously defined and X′′′ is —NH—, which comprises reacting the corresponding precursor compound of formula III or III′ wherein R 3 ′′ and R 10 are as previously defined, with the corresponding R 4 ′′—NH 2 amine, and thereafter, if desired, converting the compound of formula II′′ obtained into a further compound of formula II′′ or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
  • the invention provides a compound of formula V
  • R 11 is preferably 4-pyrimidyl.
  • R 13 is alkyl it is C 1 -C 10 alkyl, preferably C 1 -C 10 alkyl, optionally substituted, preferably with one or two substituents separately selected from hydroxy, C 1 -C 4 alkoxy, amino optionally mono- or disubstituted by C 1 -C 4 alkyl or N-heterocyclyl containing from 5 to 7 ring and optionally containing a further hetero atom (e.g. O, S or N).
  • a further hetero atom e.g. O, S or N.
  • R 13 When R 13 is aryl or heteroaryl either of which is optionally substituted up to 4 substituents, R 13 may comprise one of the customary aryl or heteroaryl substituents in the art and may be substituted as is customary in the art; for instance as defined for the substituent R 3 of WO 93/03297.
  • R 13 may comprise a phenyl, pyridyl or pyrimidyl, substituent optionally substituted by up to S substituents separately selected from C 1 -C 4 alkyl halogen, halo-substituted C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted ammo.
  • R 13 When R 13 is substituted amino it may be substituted by one or two substitutents independently selected from C 1 -C 4 alkyl C 6 -C 18 aryl, C 3 -C 18 heteroaryl C 6 -C 18 arylC 1 -C 4 alkyl, C 3 -C 18 heteroarylC 1 -C 4 alkyl, all of which are optionally substituted by halo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 4 alkoxycarbonyl.
  • R 13 is cycloalkyl it is preferably C 3 -C 8 , especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, preferably with up to 2 substituents separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • C 3 -C 8 especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, preferably with up to 2 substituents separately selected from C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • R 13 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N, optionally substituted, e.g. by up to 2 substituents, selected from halogen, hydroxy, alkoxy, or optionally mono- or di-C 1 -C 4 alkyl substituted amino.
  • R 13 may be an optionally substituted morpholino, piperazyl or piperidyl substituent.
  • R 14 When R 14 is aryl it is preferably phenyl. When R 14 is cycloalkyl, it is preferably C 3 -C 7 cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R 14 may be unsubstituted or substituted, conveniently mono-substituted, e.g.
  • phenyl conveniently meta or para substituted, by halogen, C 1 -C 4 alkyl, halo-substitued C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, optionally mono- or di-N—C 1 -C 4 alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
  • —Y— is C 1 -C 4 -alkylene, it is preferably C 1 -C 2 alkylene, and is optionally substituted, e.g. by C 1 -C 4 alkyl (e.g. methyl), halogen, hydroxy, C 1 -C 4 alkoxy, or amino.
  • R 12 is phenyl substituted with 1-3 substituents, preferably mono-substituted, selected from halogen, CN, halo-substituted alkyl, e.g. CF 3 , C 1 -C 4 alkyl, or C 1 -C 4 alkoxy.
  • R 2 is phenyl mono-substituted by halogen, e.g. 4-flurophenyl.
  • R 13 is pyridyl, pyrimidyl, piperazyl, piperidyl, —NR 9 R 10 , —CH 2 OH, —CH 2 NR 15 R 16 , —CH 2 CH 2 R 15 R 16 , or Het-C 1-4 alkyl-,
  • X is —NH—Y′—, —O— or —S—, where Y′ is —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )— or a direct bond.
  • X is NH—Y′′—, where Y′′ is —CH(CH 3 )— or a direct bond.
  • the invention provides a compound of formula V′
  • R 14 ′ is phenyl or cyclopentyl, cyclobutyl or cyclopropyl.
  • R 10 is halogen
  • X′′ is —NH—Y′′ where Y′′ is —CH(CH 3 )— or a direct bond.
  • the Invention includes the following compounds:
  • novel imidazopyridines of the invention in particular the compounds of formulae V and V′ and the specific compounds listed above are hereinafter also referred to as “Agents of the Invention”.
  • Agents of the Invention may contain at least 1 assymetric carbon atom; for instance when Y is substituted alkylene, e.g. when Y′′ is —CH(CH 3 )— for the compounds of formula II′ or V′ above.
  • the resulting diastereomers and enantiomers are encompassed by the instant invention.
  • the compounds of formula I are provided in pure or substantially pure epimeric form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms).
  • Preferred epimeric compounds of formula I are described hereinafter in the Examples.
  • Agents of the Invention which comprise free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention.
  • Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups.
  • Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
  • Agents of the Invention may also exist in the form of pharmaceutically acceptable salts, and as such are included within the scope of the invention.
  • Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, e.g., hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as arginine and lysine.
  • pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
  • metal or ammonium salts such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
  • R 11 , R 12 , R 14 and X are as previously defined and R 13 ′′ is —CH 2 CH 2 NR 15 R 16 or —CH 2 —CH 2 -Het wherein R 15 , R 16 and Het are as defined above may be prepared by reacting a corresponding vinyl precursor compound of formula VI wherein R 11 , R 12 , R 14 and X are as previously defined, with the corresponding amine of formula HNR 15 R 16 or N-heterocycloalkyl ring compound For instance the reaction may be carried out by refluxing the reactants, e.g. in acetic acid, followed by treatment with a mild base, e.g. Na 2 CO 3 .
  • a mild base e.g. Na 2 CO 3
  • the precursor compound of formula VI may be prepared by reacting the corresponding 5-chloro-imidazopyridine of formula VII
  • R 11 , R 12 , R 14 and X as are as previously defined, with a vinylating agent.
  • a vinylating agent For instance the chloro compound of formula VII is reacted with vinyltributylstannane in the presence of PdCl 2 (PPh 3 ) 2 in xylene at elevated temperature, e.g. 160° C., under an inert atmosphere.
  • Agents of the Invention of formula V, wherein R 13 is aryl or heteroaryl may be prepared from chloroprecursor compounds of formula VII, as defined above, by arylation or heteroarylation.
  • the compound of formula VII is heated with the corresponding trialkylstannyl-aryl or -heteroaryl, e.g. tributylstannylaryl- or trimethylstannyl-aryl or -heteroaryl, compound e.g. to about 150° C. under an inert atmosphere.
  • Agents of the Invention of formula V, where R 13 is —N-heterocycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, —NH—(C 1 -C 4 alkyl)-aryl, —NH—(C 1 -C 4 alkyl)-heteroaryl, or —NH—(C 1 -C 4 alkyl)-heterocycloalkyl may be prepared from chloroprecursor compounds of formula VII, as defined above, by coupling with the corresponding N-heterocycloalkyl compound or amine. The coupling reaction may carried out using Buchwald chemistry.
  • the compounds of formula VII in which X is —NH— may be prepared by reacting the corresponding methylsulphinyl compound of formula VIII
  • R 11 and R 12 are as previously defined, with the corresponding amine of formula R 14 —NH 2 .
  • the reactants are mixed and heated, e.g. to 80° C. for 1 h.
  • R 11 and R 12 are as previously defined; for instance, by treating the compound of formula IX in solution, e.g. CH 2 Cl 2 /HOAc solution, with mCPBA, e.g. at 0° C. for 30 min., followed by treatment with mild base, e.g. Na 2 CO 3 .
  • solution e.g. CH 2 Cl 2 /HOAc solution
  • mild base e.g. Na 2 CO 3
  • the methylthio compound of formula IX may be prepared by coupling the corresponding 1-H-imidazopyridine compound of formula X
  • R 12 is as defined above, with 2-methylthio-4-iodopyrimidine.
  • KN(TMS) 2 solution e.g. in toluene
  • X e.g. in DMF with mixing
  • 2-methyl-4-iodopyrimidine solution e.g. in toluene
  • the compound of formula X may be prepared by coupling 2,3-diamino-6-chloropyridine with the corresponding acid of formula R 12 COOH; for instance, by treating a mixture of the reactants with polyphosphonic acid e.g. at 150° C. for 6 h, followed by neutralisation e.g. with cold concentrated aqueous NH 3 .
  • Agents of the Invention which are 5-(4-NH-1-piperazyl)imidazopyridines of formula V in which R 13 is piperazyl and precursors therefor may be prepared by analogy to the pr paration of the compound of formula VIII′ and the precursors thereof. Conveniently the free nitrogen atom of the piperazine ring is protected e.g. with a tert. butoxycarbonyl residue, during precursor preparation as appropriate.
  • 5-(4-NH-1-piperazyl)imidazopyridines of formula I may be converted to 5-(4-substituted piperazyl)imidazopyridine Agents of the Invention as desired; for instance, as hereinafter described in the Examples.
  • the invention provides a process for the production of
  • N-Ethoxycarbonylpiperidine-4-carboxamide (6 g 30 mmol) in toluene (300 ml) is treated with Lawesson's reagent (6.1 g 15 mmol) at room teperature for 18 h.
  • the reaction mixture is evaporated and purified by SiO 2 chromatography (acetone/cyclohexane 20/80) to yield the title compound, which is recrystallised from hexanes (3.6 g 52.5%)
  • n-BuLi (10 ml of a 1.6 M solution in hexane; 12 mmol) is added at ⁇ 78° C. to a solution of diisopropylamine (2.48 ml; 17 mmol) in THF (15 ml) and stirred for 5 min.
  • 4-Methyl-2-(methylthio)pyrimidine (2 g; 14.5 mmol)-dissolved in THF (2 ml) is added dropwise and stirred for 30 min at ⁇ 78° C.
  • 4-Fluoro-N-methoxy-N-methylbenzamide (2.66 g; 14.5 mmol) is dissolved in THF (3 ml) and added slowly to the reaction mixture. The mixture is warmed to r.t.
  • reaction mixture was combined with 6M HCl in propanol (15 ml), homogenized by vigorous stirring, poured on 2N NaOH and extracted twice with CH 2 Cl 2 .
  • the combined organic phases were dried over Na 2 SO 4 , filtered, evaporated to dryness and purified by SiO 2 chromatography (tert.butyl methyl ether/MeOH/NH 3 conc. 80/18/2) to yield the title compound (1.2 g 71%) as a white foam.
  • 2,3-Diamino-6-chloropyridine (Davos-Bulk supplier, 2.25 g 15.6 mmol) and 4-fluorobenzoic acid (2.62 g 18.7 mmol) are treated with polyphosphoric acid (56.4 g) at 150° C. for 6 h.
  • the reaction mixture is poured on ice-water/NH 3 conc. and extracted with ethyl acetate three times.
  • the combined organic phases are dried over Na 2 SO 4 , filtered and evaporated to dryness to yield the crude product, which is purified by recrystallisation from ethyl acetate/tert.butyl methyl ether to yield the title compound (1.8 g 44%) as grey crystals.
  • the crystalline title compound (48 mg 50%) is prepared by analogy to the previous example.
  • the crystalline title compound (78 mg 66%) is prepared by analogy to the previous example.
  • the white crystalline title compound (1.3 g 70%) is obtained by analogy to the previous example with the exception that 4-trimethylstannylpyridine was used in the coupling reaction.
  • 2,3,6-Triaminopyridine (Austin Products; 372 mg 3 mmol) and 4-fluorobenzoic acid (420 mg 3 mmol) are treated with polyphosphoric acid (30 g) at 150° C. for 1 h.
  • the reaction mixture is poured on ice-water/NH 3 conc. and extracted with ethyl acetate three times.
  • the combined organic phases are dried over Na 2 SO 4 , filtered and evaporated to dryness to yield the crude product, which is purified by SiO 2 chromatography (acetone/cyclohexane 20/80 to 50/80) and rendered the title compound as pale yellow crystals (200 mg 29%)
  • the title compound is prepared from the sulfoxide (60 mg 0.16 mmol) in the above procedure and cyclopentylamine (0.8 ml) by heating to 120° C. for 1 h and purifying over RP18 (CH 3 CN/Water 70/30 to 10/90). The title compound is obtained as a yellow powder (30 mg 44%)
  • 6-Amino-2-chloro-5-nitropyridine (Acros, 3.66 g 21 mmol) and 1-ethoxycarbonylpiperazine (6.36 g 42 mmol) in isopropanol (85 ml) are refluxed for 3 h.
  • the reaction mixture with a yellow precipitate is poured on water/Na 2 CO 3 and extracted twice with methylene chloride.
  • the combined organic phases are dried over Na 2 SO 4 , filtered and evaporated to dryness to yield the title compound as yellow crystals, which are purified by recrystallisation from tert.-butyl methyl ether (5.5 g 89%).
  • reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times.
  • the combined organic phases are washed with 2N Na 2 CO 3 , dried over Na 2 SO 4 and evaporated to dryness.
  • Purification via SiO 2 chromatography (TBME/hexane 6:4 to 10:0) and recrystalisation from TBME yields the title compound as colorless crystals (50 mg. 50%).
  • reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times.
  • the combined organic phases are washed with 2N Na 2 CO 3 , dried over Na 2 SO 4 and evaporated to dryness.
  • Purification via SiO 2 chromatography (TBME/hexane 7:3 to 10:0) and recrystallisation from TBME yields the title compound as colorless crystals (22 mg: 19%).
  • Agents of the Invention as defined above, e.g., of formula I, II and V particularly as exemplified, in free or pharmaceutically acceptable acid addition salt form, exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy, in the treatment of diseases and conditions as hereinafter set forth.
  • Agents of the Invention possess p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity.
  • the Agents of the Invention act to inhibit production of inflammatory cytokines, such as TNF- ⁇ and IL-1, and also to potentially block the effects of these cytokines on their target cells.
  • the substrate (GST-ATF-2; a fusion protein comprising amino acids 1-109 of ATF-2 and the GST protein obtained by expression in E. coli ) is coated onto the wells of microtiter plates (50 ⁇ l/well; 1 ⁇ g/nd in PBS/0.02% Na azide) overnight at 4° C. The following day, the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide and are blocked with PBS/2% BSA/0.02% Na Azide for 1 h at 37° C. Plates are washed again 4 times with PBS/0.5% Tween 20/0.02% Na azide. The kinase cascade reaction is then started by adding the following reactants in 10 ⁇ l aliquots to a final reaction volume of 50 ⁇ l.
  • Agents of the Invention typically have IC 50 s for p38 MAP kinase inhibition in the range from about 100 nM to about 5 nM or less when tested in the above assay.
  • hPBMCs Human peripheral blood mononuclear cells
  • TNF- ⁇ in the supernatant is measured using a commercial ELISA (Innotest hTNFa, available from Innogenetics N.V., Zwijnaarde, Belgium). Agents of the Invention are tested at concentrations of from 0 to 10 MM. Exemplified Agents of the Ivention typically suppress TNF release in this assay with an IC 50 of from about ? nM to about ? nM or less when tested in this assay.
  • LPS lipopolysaccharide
  • TNF- ⁇ soluble tumour necrosis factor
  • LPS (20 mg/kg) is injected i.v. into OF1 mice (female, 8 week old).
  • One (1) hour later blood is withdrawn from the animals and TNF levels are analysed in the plasma by an EUSA method using an antibody to TNF- ⁇ Using 20 mg/kg of LPS levels of up to 15 ng of TNF- ⁇ /ml plasma are usually induced.
  • Compounds to be evaluated are given either orally or s.c. 1 to 4 hours prior to the LPS injection. Inhibition of LPS-induced TNF-release is taken as the readout.
  • Agents of the Invention typically inhibit TNF production to the extent of up to about 50% or more in the above assay when administered at 10 mg/kg p.o.
  • Agents of the Invention are potent inhibitors of TNF- ⁇ release. Accordingly, the Novel Compounds have pharmaceutical utility as follows:
  • Agents of the Invention are useful for the prophylaxis and treatment of diseases or pathological conditions mediated by cytokines such as TNF ⁇ and IL-1, e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection, e.g. a for the treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants and for the prevention of graft-versus-host disease, such as following bone marrow transplants.
  • cytokines such as TNF ⁇ and IL-1
  • inflammatory conditions e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection
  • graft-versus-host disease such as following bone marrow transplants.
  • Agents of the Invention are particularly useful for the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • Specific auto-immune diseases for which Agents of the Invention may be employed include autoimmune haematological disorders (including e.g.
  • hemolytic anaemia aplastic anaemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g.
  • ulcerative colitis and Crohn's disease endocrine ophthalmopathy
  • Graves disease sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or mini change nephropathy).
  • Agents of the Invention are also useful for the treatment, prevention, or amelioration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.
  • Agents of the Invention are useful for treating undesirable acute and hyperacute inflammatory reactions which are mediated by TNF, especially by TNF ⁇ , e.g., acute infections, for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especially AIDS-related cachexia, e.g., associated with or consequential to HIV infection.
  • acute infections for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns
  • cachexia or wasting syndrome associated with morbid TNF release consequent to infection, cancer, or organ dysfunction
  • AIDS-related cachexia e.g., associated with or consequential to HIV infection.
  • Agents of the Invention are also useful for the treatment of neurodegenerative diseases, such as Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis including demyelation and oligiodendrocyte loss in multiple sclerosis and inflammatory nervous system diseases, such as neuroinflammatory and stroke.
  • neurodegenerative diseases such as Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis including demyelation and oligiodendrocyte loss in multiple sclerosis and inflammatory nervous system diseases, such as neuroinflammatory and stroke.
  • Agents of the Invention are particularly useful for treating diseases of bone metabolism including osteoarthritis, osteoporosis and other inflammatory arthritides.
  • an indicated daily dosage is in the range of from about 50 to about 750 mg of an Agent of the Invention administered orally once or, more suitably, in divided dosages two to four times/day.
  • the Agents of the Invention may be administered by any conventional route, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions.
  • Normally for systemic administration oral dosage forms are preferred, although for some indications the Agents of the Invention may also be administered topically or dermally, e.g. in the form of a dermal cream or gel or like preparation or, for the purposes of application to the eye, in the form of an ocular cream, gel or eye-drop preparation; or may be administered by inhalation, e.g., for treating asthma
  • Suitable unit dosage forms for oral administration comprise e.g. from 25 to 250 mg of Agent of the Invention per unit dosage.
  • a method of inhibiting production of soluble TNF, especially TNF ⁇ , or of reducing inflammation in a subject i.e., a mammal, especially a human
  • a subject i.e., a mammal, especially a human
  • which method comprises administering to said subject an effective amount of an Agent of the Invention, or a method of treating any of the above mentioned conditions, particularly a method of treating an inflammatory or autoimmune disease or condition, e.g. rheumatoid arthritis, or alleviating one or more symptoms of any of the above mentioned conditions.
  • An Agent of the Invention for use as a pharmaceutical, e.g. for use as an immunosuppressant or antiinflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
  • a pharmaceutical composition comprising an Agent of the Invention in association with a pharmaceutically acceptable diluent or carrier, e.g., for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
  • a pharmaceutically acceptable diluent or carrier e.g., for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

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Abstract

Compounds of formula (I)
Figure US06891039-20050510-C00001
and pharmaceutically-acceptable and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof, wherein the symbols are as defined are MAP kinase inhibitors, useful pharmaceutically for treating TNFα and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.

Description

This application is a divisional of U.S. patent application Ser. No. 10/111,233 filed Apr. 22, 2002 now U.S. Pat. No. 6,608,072 which is a 371 of PCT/EP00/10528 filed Oct. 25, 2000.
This invention relates to heterocyclic compounds, in particular to thiazoles and imidazopyridines and to their use for treating TNFα and IL-1 mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
Accordingly the present invention provides a compound of formula I
Figure US06891039-20050510-C00002
wherein Nu is a heterocyclic nucleus selected from a thiazole in which the R1, R2 and R3 substituents are disposed as indicated below
Figure US06891039-20050510-C00003
and an imidazo[4,5-b]pyridine in which the R1, R2 and R3 substituents are disposed as indicated below
Figure US06891039-20050510-C00004
    • wherein
    • R1 is pyrimidyl or pyridyl;
    • X is —NR6—Y—, —O— or —S—,
      • where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and —Y— is C1-C4alkylene or a direct bond;
    • R2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
      • halo,
      • CF3,
      • cyano,
      • amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued,
      • carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester, optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5 cycloalkyl-substituted-carbonyl or -thiocarbonyl,
      • optionally halo-substituted-C1-C4alkoxy, C2-C4alkenoxy, C2-C4alkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
      • optionally halo substituted C1-C4 alkyl,
      • oxycarbonyl or optionally N—C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof),
      • optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-N—C1-C4 alkyl substituted,
      • optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally N—C1-C4alkyl-substituted amino carbonyl or -thiocarbonyl,
      • optionally N—C1-C4alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by
        • optionally mono- or di-N—C1-C4alkyl-substituted amino,
        • a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued, or
      • sulphinyl or sulphonyl optionally substituted by
        • optionally halo-substituted-C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
        • optionally mono- or di-C1-C4alkyl-substituted amino,
        • a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued;
    • R3 is H, amino, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C6-C18aryl, C3-C18heteroaryl, C6-C18arylC1-C4alkyl, C3-C18 heteroarylC1-C4alkyl, C3-C18heterocycloalkyl or optionally mono- or di-C1-C4alkyl substituted amino or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally a further hetero atom selected from O, S or N, all of which are further optionally substituted halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl;
    • R4 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4allyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
      and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof .
Above and elsewhere in the present description the terms halo or halogen denote I, Br, Cl or F.
Above and elsewhere in the present description the terms such as “C3-C18heteroaryl, C4-C19heteroaralkyl and C3-C18heterocycloalkyl” denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom e.g. N, O or S, and which in the case of C4-C19heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.
In particular embodiments the invention provides a compound of formula II
Figure US06891039-20050510-C00005
    • wherein
    • Z is N or CH;
    • X is —NR6—Y—, —O— or —S—,
      • where R6 is H, C1-C4alkyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and —Y— is C1-C4alkylene or a direct bond;
    • R2′ is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF3, cyano, amido or thioamido, carboxylate or thiocarboxylate, C1-C4alkoxy, C1-C4alkyl, or NH2 which is optionally mono- or di-C1-C4 alkyl substituted;
    • R3′ is H, C1-C10alkyl C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl each of which is optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
    • R4′ is C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C1-4alkyl, halogen, halo-substitued-C1-4alkyl, hydroxy, C1-4alkoxy, C1-4alkylthio, or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
      and pharmaceutically-acceptable and cleavable esters thereof and acid addition salts thereof.
When R3′ is aryl, it is preferably heteroaryl, e.g. pyridyl (e.g. 4-pyridyl) or pyrazyl, each optionally substituted, e.g. by 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R3′ is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R3′ is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R4′ is aryl it is preferably phenyl. When R′4 is cycloalkyl, it is preferably C3-C7 cycloalkyl e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R′4 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C4alkyl, halo-substituedC1-C4alkyl, C1-C4alkoxy, hydroxy or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
When Y is C1-C4 alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, C1-C4alkoxy, or amino.
More preferably R′2 is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-1-yl, or 3-CF3, 3-Cl, or 3,4-difluoro substituted phenyl.
More preferably R′3 is H, C1-C6alkyl, phenyl, pyridyl, morpholinyl, piperidyl, piperazyl, or optionally mono- or di-C1-4alkyl substituted amino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
Preferably X is —NH—Y′—, —O— or —S—, where Y′ is —CH2—, —CH2—CH2—, —CH(CH3)— or a direct bond
Thus in preferred embodiments the invention provides a compound of formula II′
Figure US06891039-20050510-C00006
    • wherein
    • R4″ is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy, trihalomethyl or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
    • R10 is halogen, cyano, amido, thioamide, amino or C1-C4alkyl;
    • R3″ is H, C1-C4alkyl, phenyl pyridyl, morpholinyl, piperidyl piperazyl, or optionally mono- or di-C1-4alkyl substituted amino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino;
    • Z is N or CH and
    • X″ is —NH—Y′—, —O— or —S—, where Y′ is —CH2—, —CH2—CH2—, —CH(CH3)— or a direct bond,
      and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably R4″ is unsubstituted or monosubstituted by halogen, C1-C4alkyl (e.g. methyl), C1-C4alkoxy (e.g. methoxy), hydroxy or CF3.
Preferably R10 is halogen, e.g. F.
Preferably X″ is —NH—Y′ where Y′ is —CH(CH3)—.
The Invention includes the following compounds:
    • 4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidinyl)-2-(4-methyl-piperidine-1-yl)thiazole;
    • 4-(4-Fluorophenyl)-5-(2-[1-(S)-phenylethyl]amino-4-pyrimidinyl)-2-(4-NH-piperidine-1-yl)thiazole;
    • 4-(4-Fluorophenyl)-2-(4-methylpiperidine-1-yl)-5-(2-[cyclopropyl-methyl]amino-4-pyridinyl)thiazole and
    • 4-(4-Fluorophenyl)-2-(4-NH-piperidine-1-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole;
The novel thiazoles of the invention, in particular the compounds of formulae II and II′ and the specific compounds listed above are hereinafter referred to “Agents of the Invention”.
Agents of the Invention of formula II″
Figure US06891039-20050510-C00007
wherein R3″, R5″, R10 and Z are as previously defined and X′″ is —NH—, may be prepared by reacting the corresponding precursor compound of formula III ml or III′
Figure US06891039-20050510-C00008
wherein R3″ and R10 are as previously defined, with the corresponding R4″—NH2 derivative. For example, the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane. Thereafter, if desired, the compound of Formula II″ obtained may be converted into a further compound of Formula II″ or otherwise treated as required.
The precursor compound of formula III may be prepared by controlled oxidation of the corresponding 5(2-methylthio-4-pyrimidinyl)-4-phenythiazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride. The corresponding 5(-4-pyrimidinyl/pyridinyl)-4-phenylthiazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula IV or IV′
Figure US06891039-20050510-C00009
wherein R10 is as defined above, with a corresponding thioamide of formula R3′C(S)NH2, typically at elevated temperature. The compounds of formula IV and IV′ may be prepared by bromination of the corresponding acetophenone, e.g. 2-(2-methylthio-4-pyrimidinyl)acetophenone. The acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N-methylbenzamide with the corresponding pyrimidine, e.g. 4methyl-2-(methylthio) pyrimidine, for instance in a THF containing organic solvent with cooling.
Thus in a further aspect the invention includes a process for the preparation of a compound of formula II″
Figure US06891039-20050510-C00010
wherein R3″, R4″, R10 and Z are as previously defined and X′″ is —NH—, which comprises reacting the corresponding precursor compound of formula III or III′
Figure US06891039-20050510-C00011
wherein R3″ and R10 are as previously defined, with the corresponding R4″—NH2 amine, and thereafter, if desired, converting the compound of formula II″ obtained into a further compound of formula II″ or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
In further particular embodiments the invention provides a compound of formula V
Figure US06891039-20050510-C00012
    • wherein
    • R11 is pyrimidyl;
    • X is —NR6—Y—, —O— or —S—,
      • where R6 is H, C1-C4acyl, C3-C8cycloalkyl, C3-C8cycloalkylC1-C3alkyl C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl and —Y— is C1-4alkylene or a direct bond;
    • R12 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
      • halo,
      • CF3,
      • cyano,
      • amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued,
      • carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester,
      • optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5 cycloalkyl-substituted-carbonyl or -thiocarbonyl,
      • optionally halo-substituted-C1-C4alkoxy, C2-C4alkenoxy, C2-C4alkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
      • optionally halo substituted C1-C4 alkyl,
      • oxycarbonyl or optionally N—C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof),
      • optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-N—C1-C4 alkyl substituted,
      • optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally N—C1-C4alkyl-substituted amino-carbonyl or -thiocarbonyl,
      • optionally N—C1-C4alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by
        • optionally mono- or di-N—C1-C4alkyl-substituted amino,
        • a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted, or
      • sulphinyl or sulphonyl optionally substituted by
        • optionally halo-substituted-C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
      • optionally mono- or di-N—C1-C4alkyl-substituted amino,
        • a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted;
    • R13 is H, amino, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl all optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C6-C18aryl, C3-C18heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl, C3-C18heterocycloalkyl or optionally mono- or di-N—C1-C4alkyl substituted amino all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl;
    • R14 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N,
      and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
R11 is preferably 4-pyrimidyl.
When R13 is alkyl it is C1-C10alkyl, preferably C1-C10alkyl, optionally substituted, preferably with one or two substituents separately selected from hydroxy, C1-C4alkoxy, amino optionally mono- or disubstituted by C1-C4alkyl or N-heterocyclyl containing from 5 to 7 ring and optionally containing a further hetero atom (e.g. O, S or N).
When R13 is aryl or heteroaryl either of which is optionally substituted up to 4 substituents, R13 may comprise one of the customary aryl or heteroaryl substituents in the art and may be substituted as is customary in the art; for instance as defined for the substituent R3 of WO 93/03297. For instance, R13 may comprise a phenyl, pyridyl or pyrimidyl, substituent optionally substituted by up to S substituents separately selected from C1-C4alkyl halogen, halo-substituted C1-C4alkyl, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted ammo.
When R13 is substituted amino it may be substituted by one or two substitutents independently selected from C1-C4alkyl C6-C18aryl, C3-C18 heteroaryl C6-C18arylC1-C4alkyl, C3-C18 heteroarylC1-C4alkyl, all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl.
When R13 is cycloalkyl it is preferably C3-C8, especially C5-C6cycloalkyl (e.g. cyclohexyl), optionally substituted, preferably with up to 2 substituents separately selected from C1-C4alkyl, halogen, hydroxy, C1-C4alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino.
When R13 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N, optionally substituted, e.g. by up to 2 substituents, selected from halogen, hydroxy, alkoxy, or optionally mono- or di-C1-C4alkyl substituted amino. For instance, R13 may be an optionally substituted morpholino, piperazyl or piperidyl substituent.
When R14 is aryl it is preferably phenyl. When R14 is cycloalkyl, it is preferably C3-C7 cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R14 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, C1-C4alkyl, halo-substitued C1-C4alkyl, C1-C4alkoxy, hydroxy, optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
When —Y— is C1-C4-alkylene, it is preferably C1-C2 alkylene, and is optionally substituted, e.g. by C1-C4alkyl (e.g. methyl), halogen, hydroxy, C1-C4alkoxy, or amino.
Preferably R12 is phenyl substituted with 1-3 substituents, preferably mono-substituted, selected from halogen, CN, halo-substituted alkyl, e.g. CF3, C1-C4alkyl, or C1-C4alkoxy. Most preferably R2 is phenyl mono-substituted by halogen, e.g. 4-flurophenyl.
In particular embodiments R13 is pyridyl, pyrimidyl, piperazyl, piperidyl, —NR9R10, —CH2OH, —CH2NR15R16, —CH2CH2R15R16, or Het-C1-4alkyl-,
    • wherein
    • R9 and R10 are separately selected from H, C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl all of which are optionally substituted by halo, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl,
    • R15 and R16 are separately selected from H or C1-C4alkyl, and
    • Het is N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom (e.g. O, S or N).
Preferably X is —NH—Y′—, —O— or —S—, where Y′ is —CH2—, —CH2—CH2—, —CH(CH3)— or a direct bond. Most preferably X is NH—Y″—, where Y″ is —CH(CH3)— or a direct bond.
Thus in preferred embodiments the invention provides a compound of formula V′
Figure US06891039-20050510-C00013
    • wherein
    • R14′ is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy, trihalomethyl optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
    • R10 is halogen, CF3, C1-C4alkyl or C1-C4alkoxy;
    • R13′ is pyridyl pyrimidyl, piperazinyl piperidinyl, NR9R10, —CH2OH, CH2NR15R16, —CH2CH2R15R16, or Het-C1-C4alkyl-,
    • wherein
      • R9 and R10 are separately selected from H, C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl,
      • R11 and R12 are separately selected from H or C1-C6alkyl, and
      • Het is N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom (e.g. O, S or N)
    • X″ is —NH—Y′—, —O— or —S—, where Y′ is —CH2—, —CH2—CH2—, —CH(CH3)— or a direct bond,
      and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof.
Preferably R14′ is phenyl or cyclopentyl, cyclobutyl or cyclopropyl.
Preferably R10 is halogen.
Preferably X″ is —NH—Y″ where Y″ is —CH(CH3)— or a direct bond.
The Invention includes the following compounds:
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidino-N-2-ethyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(N,N-diethylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino-N-2-ethyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(isopropylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyrrolidino-N-2-ethyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-pyridyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-pyridyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-piperidinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-methyl-4-piperidinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-(2-hydroxy-2-methyl)propyl-4-piperidinyl)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(benzylamino)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-fluorophenyl amino)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyridyl-4-amino)imidazo[4,5-b]pyridine;
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-ethoxycarbonyl piperidine-4-amino)imidazo[4,5-b]pyridine, and
  • 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidine-4-amino)imidazo[4,5-b]pyridine.
The novel imidazopyridines of the invention, in particular the compounds of formulae V and V′ and the specific compounds listed above are hereinafter also referred to as “Agents of the Invention”.
It will be appreciated that certain Agents of the Invention may contain at least 1 assymetric carbon atom; for instance when Y is substituted alkylene, e.g. when Y″ is —CH(CH3)— for the compounds of formula II′ or V′ above. The resulting diastereomers and enantiomers are encompassed by the instant invention. Preferably, however, e.g. for pharmaceutical use in accordance with the invention, the compounds of formula I, are provided in pure or substantially pure epimeric form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms). Preferred epimeric compounds of formula I are described hereinafter in the Examples.
The Agents of the Invention which comprise free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups. Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
Agents of the Invention may also exist in the form of pharmaceutically acceptable salts, and as such are included within the scope of the invention. Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, e.g., hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as arginine and lysine. For compounds of the invention having acidic groups, for example, a free carboxy group, pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
Agents of the Invention of Formula V″
Figure US06891039-20050510-C00014
wherein R11, R12, R14 and X are as previously defined and R13″ is —CH2CH2NR15R16 or —CH2—CH2-Het wherein R15, R16 and Het are as defined above may be prepared by reacting a corresponding vinyl precursor compound of formula VI
Figure US06891039-20050510-C00015
wherein R11, R12, R14 and X are as previously defined, with the corresponding amine of formula HNR15R16 or N-heterocycloalkyl ring compound For instance the reaction may be carried out by refluxing the reactants, e.g. in acetic acid, followed by treatment with a mild base, e.g. Na2CO3.
The precursor compound of formula VI may be prepared by reacting the corresponding 5-chloro-imidazopyridine of formula VII
Figure US06891039-20050510-C00016
wherein R11, R12, R14 and X as are as previously defined, with a vinylating agent. For instance the chloro compound of formula VII is reacted with vinyltributylstannane in the presence of PdCl2(PPh3)2 in xylene at elevated temperature, e.g. 160° C., under an inert atmosphere.
Agents of the Invention of formula V, wherein R13 is aryl or heteroaryl may be prepared from chloroprecursor compounds of formula VII, as defined above, by arylation or heteroarylation. For instance the compound of formula VII is heated with the corresponding trialkylstannyl-aryl or -heteroaryl, e.g. tributylstannylaryl- or trimethylstannyl-aryl or -heteroaryl, compound e.g. to about 150° C. under an inert atmosphere.
Agents of the Invention of formula V, where R13 is —N-heterocycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, —NH—(C1-C4alkyl)-aryl, —NH—(C1-C4alkyl)-heteroaryl, or —NH—(C1-C4alkyl)-heterocycloalkyl may be prepared from chloroprecursor compounds of formula VII, as defined above, by coupling with the corresponding N-heterocycloalkyl compound or amine. The coupling reaction may carried out using Buchwald chemistry. For instance, to a solution of the chloroprecursor compound of formula VII and a suitable ligand, e.g. BINAP, in an inert organic solvent such as xylene is added the N-heterocycloalkyl compound or amine together with an organic base, e.g. sodium tertiary butylate, and the reaction mixture heated, e.g. to 160° C. for 10 minutes under argon; after which the product may be recovered by pouring the reaction mixture onto water and solvent extraction, e.g. with TBME.
The compounds of formula VII in which X is —NH— may be prepared by reacting the corresponding methylsulphinyl compound of formula VIII
Figure US06891039-20050510-C00017
wherein R11 and R12 are as previously defined, with the corresponding amine of formula R14—NH2. For instance, the reactants are mixed and heated, e.g. to 80° C. for 1 h.
The methylsulphinyl compound of formula VIII prepared by oxidation of the corresponding methylthio compound of formula IX.
Figure US06891039-20050510-C00018
wherein R11 and R12 are as previously defined; for instance, by treating the compound of formula IX in solution, e.g. CH2Cl2/HOAc solution, with mCPBA, e.g. at 0° C. for 30 min., followed by treatment with mild base, e.g. Na2CO3.
The methylthio compound of formula IX may be prepared by coupling the corresponding 1-H-imidazopyridine compound of formula X
Figure US06891039-20050510-C00019
wherein R12 is as defined above, with 2-methylthio-4-iodopyrimidine. For instance, KN(TMS)2 solution, e.g. in toluene, is added at 0° C. to a solution of X, e.g. in DMF with mixing, and 2-methyl-4-iodopyrimidine solution e.g. in toluene, is added and the reaction mixture heated e.g. at 120° C. for 20 h.
The compound of formula X may be prepared by coupling 2,3-diamino-6-chloropyridine with the corresponding acid of formula R12COOH; for instance, by treating a mixture of the reactants with polyphosphonic acid e.g. at 150° C. for 6 h, followed by neutralisation e.g. with cold concentrated aqueous NH3.
Compounds of formula V in which R13 is NH2 may be prepared by reacting the corresponding methyl sulphinyl compound of formula VIII′
Figure US06891039-20050510-C00020
    • wherein R11, and R12 are as previously defined, with the corresponding amine of formula R14—NH2, for instance, as described above for the compound of formula VI. The compound of formula VIII′ and precursors therefor may be prepared by analogy with the compound of formula VIII and the precursors thereof; for instance, as described above.
Agents of the Invention which are 5-(4-NH-1-piperazyl)imidazopyridines of formula V in which R13 is piperazyl and precursors therefor may be prepared by analogy to the pr paration of the compound of formula VIII′ and the precursors thereof. Conveniently the free nitrogen atom of the piperazine ring is protected e.g. with a tert. butoxycarbonyl residue, during precursor preparation as appropriate. 5-(4-NH-1-piperazyl)imidazopyridines of formula I may be converted to 5-(4-substituted piperazyl)imidazopyridine Agents of the Invention as desired; for instance, as hereinafter described in the Examples.
Accordingly in a further aspect the invention provides a process for the production of
  • (i) an Agent of the Invention of formula V″
    Figure US06891039-20050510-C00021
  •  wherein R11, R12, R14 and X are as previously defined and R13″ is —CH2—CH2NR15R16 or —CH2—CH2-Het wherein R15, R16 and Het are as previously defined comprising reacting a corresponding vinyl precursor of formula VI
    Figure US06891039-20050510-C00022
  •  wherein R11, R12, R14 and X are as previously defined with the corresponding amine of formula HNR15R16 or N-heterocycloalkyl ring compound;
  • (ii) an Agent of the Invention of formula V wherein R13 is aryl or heteroaryl comprising arylation or heteroarylation of a compound of formula VII
    Figure US06891039-20050510-C00023
  •  wherein R11, R12, R14 and X are as previously defined;
  • (iii) an Agent of the Invent ion of formula V wherein R13 is N-heterocycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, —NH—(C1-C4alkyl)-heterocycloalkyl, —NH—(C1-C4alkyl)-aryl, —NH—(C1-C4alkyl)-heteroaryl, or —NH—(C1-C4alkyl)-heterocycloalkyl comprising coupling a corresponding N-heterocycloalkyl compound or amine;
  • (iv) an Agent of the Invention of formula V in which R13 is —NH2, comprising reacting the corresponding methyl sulphinyl compound of formula VIII′
    Figure US06891039-20050510-C00024
    wherein R11, and R12 are as previously defined, with the corresponding amine of formula R14—NH2, and
  • (v) an Agent of the Invention of formula V in which R13 is piperazinyl comprising reacting a corresponding methylsulphinyl compound of formula VIII″
    Figure US06891039-20050510-C00025
  •  wherein R11 and R12 are as previously defined and P is an N protecting group, with the corresponding amine of formula R14—NH2.
    The synthesis of Agents of the Invention is further described in the following Examples.
EXAMPLES Example 1 (4-Fluorophenyl)-2-(piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)thiazole
a) N-Ethoxycarbonylpiperidine-4-thiocarboxamide
Figure US06891039-20050510-C00026
N-Ethoxycarbonylpiperidine-4-carboxamide (6 g 30 mmol) in toluene (300 ml) is treated with Lawesson's reagent (6.1 g 15 mmol) at room teperature for 18 h. The reaction mixture is evaporated and purified by SiO2 chromatography (acetone/cyclohexane 20/80) to yield the title compound, which is recrystallised from hexanes (3.6 g 52.5%)
1H-NMR (400 MHz; CDCl3): 1.28 (t, 3H); 1.72-1.83 (dq, 2H); 1.95 (d, 2H); 2.68-2.88 (m, 3H); 4.18 (q, 2H); 4.30 (bs, 2H); 6.92 (bs, 1H, NH); 7.51 (bs, 1H, NH)
MS (m/z) CI: 217 (MH+, 50); 171 (100).
b) 4-Fluoro-2-(2-methylthio-4-pyrimidinyl)acetophenone
Figure US06891039-20050510-C00027
n-BuLi (10 ml of a 1.6 M solution in hexane; 12 mmol) is added at −78° C. to a solution of diisopropylamine (2.48 ml; 17 mmol) in THF (15 ml) and stirred for 5 min. 4-Methyl-2-(methylthio)pyrimidine (2 g; 14.5 mmol)-dissolved in THF (2 ml) is added dropwise and stirred for 30 min at −78° C. 4-Fluoro-N-methoxy-N-methylbenzamide (2.66 g; 14.5 mmol) is dissolved in THF (3 ml) and added slowly to the reaction mixture. The mixture is warmed to r.t. within 45 min. and poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield 2.5 g (65%) of yellow crystals after recrystallisation from tert.butyl methyl ether/hexane.
1H-NMR (200 MHz CDCl3): 3.00 (s, 3H); 6.30 (s, 1H; vinyl-H of enol); 7.00 (d, 1H); 7.50 (dd, 2H); 8.20 (dd, 2H); 8.7 (d, 2H). Due to pH-dependent keto-enol tautomery, signals may be duplicated.
c) 4-Fluoro-2-bromo-2-(2-methylthio-4-pyrimidinyl)acetophenone
Figure US06891039-20050510-C00028
Bromine (1.22 g; 7.6 mmol) in acetic acid (5.6 ml) is added to a solution of 4-Fluoro-2-(2-methylthio-4-pyrimidinyl)acetophenone (2 g; 7.6 mmol) in acetic acid (40 ml). The initially thick precipitate is almost dissolved after 20 min., filtered and the filtrate evaporated to dryness. The residue is taken up in a saturated solution of NaHCO3 and extracted three times with tert.butyl methyl ether. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield 2.6 g (100%) of a brown oil, which is used in the next step without purification.
d) 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(methylthio-4-pyrimidinyl)thiazole
Figure US06891039-20050510-C00029
Na2SO4 (6.9 g 40 mmol) in DMF (100 ml) is heated at 120° C. for 1 min. N-Ethoxycarbonyl-piperidine-4-thiocarboxamide (8.6 g 40 mmol) is added as a solid and heating continued for 5 min. 2-Bromo-2-(2-methylthio-4-pyrimidinyl)-1-(4-fluorophenyl)ethanone (6.8 g 20 mmol) in DMF (20 ml) is rapidly added within 3 seconds and stirring continued at 120° C. for 10 min. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate/hexanes 5/95 to 10/90) to yield the title compound as yellow crystals (2.2 g 24%)
1H-NMR (400 MHz; CDCl3): 1.31 (t, 3H); 1.78-1.92 (dq, 2H); 2.21 (bd, 2H); 2.58 (s, 3H); 2.91-3.03 (bt, 2H); 3.18-3.28 (m, 1H); 4.20 (q, 2H); 4.25-4.40 (bs, 2H); 6.75 (d, 1H); 7.15 (t, 2H); 7.57 (dd, 2H); 8.31 (d, 1H). MS (m/z) ESI: 459 (MH+, 100).
e) 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(methylsulfinyl-4-pyrimidinyl)thiazole
Figure US06891039-20050510-C00030
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(methylthio-4-pyrimidinyl)thiazole (4.0 g 8.7 mmol) in CH2C12 (80 ml) is treated with mCPBA (70% 2.1 g 8.7 mmol) at 0° C. for 15 min. The reaction mixture is poured on 2N Na2CO3 and extracted with CH2Cl2 three times. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (acetone/hexanes 20/80 to 50/80) to yield the title compound (2.2 g 53%) as a white foam.
1H-NMR (400 MHz; CDCl3): 1.31 (t, 3H); 1.78-1.92 (dq, 2H); 2.21 (bd, 2H); 3.00 (s, 3H); 2.90-3.02 (m, 2H); 3.20-3.30 (bt, 1H); 4.18 (q, 2H); 4.25-4.40 (bs, 2H); 7.15 (d, 1H); 7.20 (t, 2H); 7.56 (dd, 2H); 8.63 (d, 1H). MS (m/z) ESI: 475 (MH+).
f) 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)thiazole
Figure US06891039-20050510-C00031
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(methylsulfinyl-4-pyrimidinyl)thiazole (2.2 g 4.6 mmol) and 1-(S)-phenylethylamine (2.2 ml) are heated at 100° C. for 1 h. Purification over SiO2 (acetone/cyclohexane 10/90 to 20/80) yielded the title compound as a pale yellow foam (2.4 g 95%).
1H-NMR (400 MHz; CDCl3): 1.31 (t, 3H); 1.51 (d, 3H); 1.75-1.88 (bq, 2H); 2.18 (bd (2H); 2.97 (bt, 2H); 3.20 (tt, 1H); 4.20 (q, 2H); 4.30 (bs, 2H); 5.17 (m, 1H); 5.46 (d, 1H, NH); 6.35 (d, 1H); 7.12 (t, 2H); 7.30-7.45 (m, 5H); 7.55 (dd, 2H); 8.08 (d, 1H). MS (m/z) ESI: 523 (MH+, 100).
g) 4-(4-Fluorophenyl)-2-(Piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl) thiazole
Figure US06891039-20050510-C00032
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)thiazole (2.4 g 4.5 mmol) was dissolved in CHCl3 (45 ml) and treated with Me3SiI (1.8 ml 13.5 mmol) at 60° C. for 6 h. The reaction mixture was combined with 6M HCl in propanol (18.5 ml), homogenized by vigorous stirring, poured on 2N NaOH and extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5 to 80/18/2) to yield the title compound (1.8 g 87%) as a white foam.
1H-NMR (400 MHz; CDCl3): 1.51 (d, 3H); 1.75-1.88 (bq, 2H); 2.18 (bd (2H); 2.82 (dt, 2H); 3.18 (tt, 1H); 3.25 (d, 2H); 5.17 (nm 1H); 5.45 (d, 1H, NH); 6.32 (d, 1H); 7.12 (t, 2H); 7.30-7.47 (m, 5H); 7.56 (dd, 2H); 8.07 (d, 1H). MS (m/z) ESI: 460 (MH+, 100).
Example 2 4-(4-Fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)thiazole
Figure US06891039-20050510-C00033
4-(4-Fluorophenyl)-2-(piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl) thiazole (575 mg 1.25 mmol) is dissolved in MeOH (12 ml) and treated with an aqueous 36%-solution of formaldehyde (0.2 ml 2.5 mmol and NaBH4 (95 mg 2.5 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5 to 90/9/1) to yield the title compound (600 mg 85%) as pale yellow foam.
1H-NMR (400 MHz; CDCl3): 1.51 (d, 3H); 1.88-2.01 (m, 2H); 2.08-2.25 (m, 4H); 2.48 (s, 3H); 2.97-3.08 (m, 3H); 5.18 (m, 1H); 5.48 (d, 1H, NH); 6.33 (d, 1H); 7.12 (t, 2H); 7.30-7.47 (m, 5H); 7.56 (dd, 2H); 8.05 (d, 1H). MS (m/z) ESI: 474 (MH+, 100).
Example 3 4-(4-Fluorophenyl)-2-(piperidin-4-yl).5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole
a) 4-Fluoro-2-(2-fluoropyridin-4-yl)acetophenone
Figure US06891039-20050510-C00034
Diisopropylamine (0.93 ml; 6.55 mmol) in THF (6 nm)is cooled to −78° C. and treated with nBuLi (3.8 ml; 6.08 mmol of a 1.6 M solution in hexane). 2-Fluoro-4-methylpyridine (620 mg; 5.4 mmol) is added dropwise and stirred under argon for 30 min. 4-Fluoro-N-methoxy-N-methylbenzamide (1 g; 5.46 mmol) is added dropwise in THF (0.5 ml) and the reaction mixture allowed to warm up to room temperature within 10 min. then poured on a saturated solution of NaCl and extracted with TOME three times. The combined organic phases are washed with water, dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as pale yellow crystals. Purification by recrystallisation from hot TBME rendered the desired compound as white solid (630 mg; 50%).
1H-NMR (200 MHz; CDCl3): 4.35 (s, 2H); 6.88 (s, 1H); 7.08-7.30 (m, 3H); 7.99-8.15 (dd, 2H); 8.20 (d, 1H). MS (e/z) ESI: 233 (M+, 5); 123 (100).
b) 4-Fluoro-2-bromo-(2-fluoropyridin-4-)acetophenone
Figure US06891039-20050510-C00035
4-Fluoro-2-(2-fluoropyridin-4-yl)acetophenone (0.5 g; 2.1 mmol) dissolved. in acetic acid (4 ml) is treated with bromine (0.34 g; 2.1 mmol) in acetic acid (1 ml) at room temperature for 2.5 h under stirring. The light brown solution is evaporated to dryness, dissolved in ether and extracted three times with diethyl ether The combined organic phases are washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as pale yellow oil (0.67 g; 100%).
1H-NMR (200 MHz; CDCl3): 6.15 (s, 1H); 7.10-7.38 (m, 4H); 8.08 (dd, 2H); 8.23 (d, 1H). MS (e/z) ESI: 232 (M−Br); 204 (10); 203 (12); 123 (100).
c) 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-fluoro-4-pyridinyl)thiazole
Figure US06891039-20050510-C00036
2-Bromo-2-(2-fluoro-4-pyridyl)-1-(4-fluorophenyl)ethanone (2.5 g 8.0 mmol) and N-ethoxycarbonyl-piperidine-4-thiocarboxamide (2.1 g 9.6 mmol) are heated at 60° C. in DMF (4 ml) for 30 min. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 100/0) to yield the title compound as an oil (2.5 g 70%)
MS (m/z) ESI: 430 (MH+)
d) 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole
Figure US06891039-20050510-C00037
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-fluoro-4-pyridinyl)thiazole (2.4 g 5.5 mmol) and 1-(S)-phenylethylamine (5.5 ml) are heated to 195° C. for 5 h. The reaction mixture is evaporated and purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 30/70) to yield the title compound as a white foam (2.0 g 67.3%)
1H-NMR (400 MHz; CDCl3): 1.31 (t, 3D; 1.55 (d, 3H); 1.72-1.87 (m, 2H); 2.17 (d, 2H); 2.98 (bt, 2H); 3.15-3.23 (m, 1H); 4.18 (q, 2H); 4.30 (bs, 2H); 4.56 (m, 1H); 5.01 (d, 1H, NH); 6.15 (s, 1H); 6.50 (d, 1H); 6.95 (dd, 2H); 7.22-7.46 (m, 5H); 7.45 (dd, 2H); 8.03 (d, 1H). MS (m/z) CI: 531 (MH+, 100).
e) 4-(4-Fluorophenyl)-2-(piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole
Figure US06891039-20050510-C00038
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole (2 g 3.7 mmol) is dissolved in CHCl3 (37 ml) and treated with Me3SiI (1.5 ml 11.1 mmol) at 60° C. for 5 h. A second portion of Me3SiI (0.75 ml 5.55 mmol) was added and stirring continued for another 3 h at 60° C. The reaction mixture was combined with 6M HCl in propanol (15 ml), homogenized by vigorous stirring, poured on 2N NaOH and extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 80/18/2) to yield the title compound (1.2 g 71%) as a white foam.
1H-NMR (400 MHz; CDCl3): 1.53 (d, 3H); 1.77 (bs, 3H); 2.17 (bd, 2H); 2.78 (bt, 2H); 3.15 (bt, 1H); 3.35 (bd, 2H); 4.55 (m, 1H); 5.00 (d, 1H, NH); 6.17 (s, 1H); 6.50 (d, 1H); 6.97 (bt, 2H); 7.20-7.37 (m, 5H); 7.45 (bt, 2H); 8.02 (d, 1H). MS (m/z) CI: 459 (MH+)
Example 4 4-(4-Fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-Phenylethyl)amino-4-pyridinyl)thiazole
Figure US06891039-20050510-C00039
4-(4-Fluorophenyl)-2-(4-piperidinyl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole (500 mg 1.09 mmol) is dissolved in MeOH (11 ml) and treated with an aqueous 36%-solution of formaldehyde (0.17 ml 2.18 mmol) and NaBH4 (83 mg 2.18 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5) to yield the title compound (550 mg 86%) as pale yellow foam.
1H-NMR (400 MHz; CDCl3): 1.53 (d, 3H); 1.83-1.98 (m, 2H); 2.07-2.20 (m, 4H); 2.35 (s, 3H); 2.98 (bd, 3H); 4.55 (m, 1H); 4.98 (d, 1H, NH); 6.15 (s, 1H); 6.50 (d, 1H); 6.98 (t, 2H); 7.22-7.35 (m, 5H); 7.45 (dd, 2H); 8.02 (d, 1H). MS (m/z) ESI: 473 (MH+)
Example 5 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidino-N-2-ethyl)imidazo-[4,5-b]pyridine
a) 5-Chloro-2-(4-fluorophenyl)imidazo-[4,5-b]pyridine
Figure US06891039-20050510-C00040
2,3-Diamino-6-chloropyridine (Davos-Bulk supplier, 2.25 g 15.6 mmol) and 4-fluorobenzoic acid (2.62 g 18.7 mmol) are treated with polyphosphoric acid (56.4 g) at 150° C. for 6 h. The reaction mixture is poured on ice-water/NH3conc. and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by recrystallisation from ethyl acetate/tert.butyl methyl ether to yield the title compound (1.8 g 44%) as grey crystals.
1H-NMR (400 MHz; DMSO-d6): 7.32 (d, 1H); 7.47 (t, 2H); 8.08 (bd, 1H); 8.28 (q, 2H); 13.6 (s, 1H). MS (m/z) ESI: 247 (MH+; 100).
b) 5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00041
KN(TMS)2 (1.42 g 7.16 mmol) in toluene (7 ml) is added at 0° C. to a solution of 5-Chloro-2-(4-fluorophenyl)imidazo[4,5b]pyridine (1.9 g 6.66 mmol) in DMF (25 ml). After stirring 1 h at room temperature, 2-methylthio-4-iodopyrimidine (1.8 g 7.1 mmol) in toluene (7 ml) is added dropwise and heated for 20 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crystalline crude product, which after recrystalisation from ethyl acetate yields the title compound as colorless crystals (1.76 g 67%).
1H-NMR (400 MHz; CDCl3): 2.58 (s, 3H); 6.57 (d, 1H); 7.18 (t, 2H); 7.36 (d, 1H); 7.68 (q, 2H); 8.17 (d, 1H); 8.53 (d, 1H) MS (m/z) ESI: 372 (MH+; 100); 352 (10); 336 (20).
The correct regiochemistry is demonstrated 2 steps later on the cyclopentylamine (d) analogue by ROESY.
c) 5-Chloro-2-(4-fluorophenyl)-1-(2-methylsulfinyl-4-pyrimidinyl)imdazo[4,5-b]pyridine
Figure US06891039-20050510-C00042
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with mCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
1H-NMR (400 MHz; CDCl3): 3.08 (s, 3H); 6.92 (d, 1H); 7.25 (t, 2H); 7.42 (d, 1H); 7.68 (q, 2H); 8.55 (d, 1H); 8.78 (bs, 1H). MS (m/z) ESI: 388 (MH+, 100); 352 (30).
d) 5-Chloro-2-(4-fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00043
5-Chloro-2-(4-fluorophenyl)-1-(2-methylsulfinyl-4-pyrimidinyl)imidazo[4,5-b]pyridine (200 mg 0.52 mmol) and cyclopentylamine (1 ml) are heated to 80° C. for 1 h, evaporated and purified by SiO2 chromatography (acetone/cyclohexane 10/90 to 20/80) to yield the title compound as white crystals (50 mg 24%).
1H-NMR (400 MHz; CDCl3): 1.43-1.86 (m, 6H); 1.95-2.20 (bs, 2H); 4.08-4.42 (bs, 1H); 5.30-5.52 (bs, 1H, NH); 6.20 (bs, 1H); 7.17 (t, 2H); 7.33 (d, 1H); 7.71 (q, 2H); 8.10 (d, 1H); 8.28 (d, 1H). The correct regiochemistry is demonstrated by ROESY. MS (m/z) ESI: 409 (MH+, 100)
e) 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-vinylimidazo[4,5-b]pyridine
Figure US06891039-20050510-C00044
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-chloroimidazo[4,5-b]pyridine (50 mg 0.12 mmol), vinyltributylstannane (4.3 ml 0.15 mmol) and PdCl2(PPh3)2 (8.6 mg 0.01 mmol) are dissolved in xylene (1 ml) and heated to 160° C. for 1 h under argon. The reaction mixture is purified over SiO2 (acetone/hexanes 15/85) to yield the title compound as colorless crystals (42 mg 86%)
1H-NMR (400 MHz; CDCl3): 1.45-1.86 (m, 6H); 1.93-2.20 (bs, 2H); 4.06-4.48 (bs, 1H); 5.35 (bs, 1H, NH); 5.53 (d, 1H); 6.21 (bs, 1H); 6.44 (d, 1H); 6.95 (q, 1); 7.18 (t, 2H); 7.48 (d, 1H); 7.73 (q, 2H); 8.08 (d, 1H); 8.30 (d, 1). MS (m/z) ESI: 399 (M−H).
f) 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidino-N-2-ethyl)imidazo-[4,5-b]pyridine
Figure US06891039-20050510-C00045
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyridinyl)-5-vinylimidazo[4,5-b]pyridine (50 mg 0.13 mmol) and piperidine (0.3 ml 3 mmol) are refluxed in HOAc (1 ml) for 1.5 h, poured on a saturated solution of Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 85/15/1) to yield the title compound (60 mg 98%) as yellow crystals.
1H-NMR (400 MHz; DMSO, 120° C: 1.40-1.90 (m, 14H); 2.55 (bs, 2H); 2.75-2.91 (n, 4H); 3.08 (t, 2H); 4.03 (m, 1H); 6.43 (d, 1H); 6.97 (bs, 1H, NH); 7.28 (t, 3H); 7.69 (dd, 2H); 8.00 (d, 1H); 8.38 (d, 1H). MS (m/z) ESI: 486 (MH+; 100)
Example 6 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(N,N-diethyl-amino-N-2-ethyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00046
The crystalline title compound (48 mg 50%) is prepared by analogy to the previous example.
1H-NMR (400 MHz; CDCl3): 1.12 (bt, 6H); 1.46-2.20 (m, 8H); 2.71 (bd, 4H); 2.97-3.20 (bd, 4H); 4.05-4.38 (bs, 1H); 5.35 (bs, 1H, NH); 6.18 (bs, 1H); 7.12 (t, 2H); 7.20 (d, 1H); 7.71 (dd, 2H); 8.03 (d, 1H); 8.29 (d, 1H). MS (m/z) ESI: 474 (MH+, 100).
Example 7 2 (4-Fluorophenyl)-1-(2cyclopentylamino-4pyrimidinyl)-5-(morpholino-N-2-ethyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00047
The crystalline title compound (78 mg 66%) is prepared by analogy to the previous example.
1H-NMR (400 MHz; CDCl3): 1.45-1.85 (m, 61); 1.93-2.13 (bs, 2H); 2.59 (bs, 4H); 2.95 (t, 2H); 3.18 (t, 2H); 3.78 (t, 4H); 4.03-4.41 (bs, 1H); 5.35 (bs, 1H, NH); 6.20 (s, 1H); 7.15 (t, 2H); 7.20 (d, 1E); 7.72 (dd, 2H); 8.05 (d, 1H); 8.30 (d, 1H). MS (m/z) ESI: 488 (MH+, 100);
Example 8 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(isopropylamino-N-2-ethyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00048
The crystalline title compound (30 mg 33%) is prepared by analogy to the previous example.
1H-NMR (400 MHz; CDCl3): 1.15 (d, 6H); 1.45-2.15 (m, 8H); 2.95 (m, 1H); 3.21 (s, 4H); 4.08-4.35 (bs, 1H); 5.38 (bs, 1H, NH); 6.20 (bs, 1H); 7.16 (t, 2H); 7.22 (d, 1H); 7.73 (dd, 2H); 8.05 (d, 2H); 8.29 (d, 1H). MS (m/z) ESI: 460 (MH+, 100).
Example 9 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyrrolidino-N-2-ethyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00049
The crystalline title compound (34 mg 36%) is prepared by analogy to the previous example.
1H-NMR (400 MHz; CDCl3): 1.45-2.18 (m, 12H); 2.65 (bs, 4H); 3.03 (m, 2H); 3.23 (m, 2H); 4.20 (bs, 1H); 5.35 (bs 1H, NH); 6.18 (bs, 1H); 7.14 (t, 2H); 7.22 (d, 1H); 7.74 (dd, 2H); 8.04 (d, 1H); 8.28 (d, 1H) MS (m)/z) ESI: 472 (M+, 100).
Example 10 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-pyridyl)imidazo-[4,5-b]pyridine
Figure US06891039-20050510-C00050
5-Chloro-2-(4-fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)imidazo[4,5-b]pyridine (2 g 4.9 mmol), 3-tributylstannylpyridine (3.6 g 9.8 mmol) and PdCl2(PPh3)2 (340 mg 0.48 mmol) are heated in xylene (50 ml) for 3 h at 150° C. under argon. The reaction mixture is filtered at 60° C. and chromatographed over SiO2 (acetone/hexanes 3/7 to 6/4) to yield pale yellow crystals (1.3 g). Recrystallisation from THF/hexanes renders the title compound as colorless crystals (985 mg 45%).
1H-NMR (400 MHz; CDCl3): 1.45-1.90 (m, 6H); 1.95-2.20 (bs, 2H); 4.08-4.45 (bs, 1H); 5.41 (bs, 1H, NH); 6.25 (bs, 1H); 7.18 (t, 2H); 7.48 (m, 1H); 7.78 (dd, 2H); 7.86 (d, 1H); 8.25 (d, 1H); 8.33 (d, 1H); 8.60 (d, 1H); 8.68 (d, 1H).9.38 (s, 1H). MS (m/z) ESI: 450 (M−H).
Example 11 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-pyridyl)imidazo-[4,5-b]pyridine
Figure US06891039-20050510-C00051
The white crystalline title compound (1.3 g 70%) is obtained by analogy to the previous example with the exception that 4-trimethylstannylpyridine was used in the coupling reaction.
1H-NMR (400 MHz; CDCl3): 1.45-1.90 (m, 6H); 1.95-2.20 (bs, 2H); 4.08-4.45 (bs, 1H); 5.41 (bs, 1H, NH); 6.25 (bs, 1H); 7.18 (t, 2H); 7.78 (dd, 2H); 7.88 (d, 1H); 8.12 (d, 2H); 8.28 (d, 1H); 8.33 (d, 1H); 8.80 (d, 2H). MS (m/z) ESI: 452.3 (MH+, 100).
Example 12 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine
a) 2-(4-Fluorophenyl)-5-aminoimidazo[4,5-b]pyridine
Figure US06891039-20050510-C00052
2,3,6-Triaminopyridine (Austin Products; 372 mg 3 mmol) and 4-fluorobenzoic acid (420 mg 3 mmol) are treated with polyphosphoric acid (30 g) at 150° C. for 1 h. The reaction mixture is poured on ice-water/NH3conc. and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 50/80) and rendered the title compound as pale yellow crystals (200 mg 29%)
1H-NMR (400 MHz; DMSO): 5.92 (bs, 2H, NH2); 6.40 (d, 1H); 7.35 (t, 2H); 7.65 (d, 1H); 8.13 (dd, 2H); 12.80 (bs, 1H, NH). MS (m/z) ESI: 229 (MH+, 100).
b) 2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]-pyridine
Figure US06891039-20050510-C00053
KN(TMS)2 (688 mg 3.65 mmol) in toluene (3.5 ml) is added at 0° C. to a solution of 2-(4-fluorophenyl)-5-aminoimidazo[4,5-b]pyridine (684 mg 3 mmol) in DMF (10 ml). After stirring 1 h at room temperature, 2-methylthio-4-iodopyrimidine (832 mg 3.3 mmol) in toluene (3.3 ml) is added dropwise and heated for 18 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 60/40) and renders the title compound as a yellow foam (300 mg 27%)
1H-NMR (400 MHz; CDCl3): 2.58 (s, 3H); 4.60 (bs, 2H, NH2); 6.55 (d, 1H); 6.59 (d, 1H); 7.16 (t, 2H); 7.63 (dd, 2H); 8.00 (d, 1H); 8.48 (d, 1H). The correct regiochemistry was demonstrated by ROESY. MS (m/z) ESI: 353 (MH+, 100).
c) 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine
Figure US06891039-20050510-C00054
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 nm), combined at 0° C. with mCPBA (84 mg 70%, 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na3SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%)
1H-NMR (400 MHz; CDCl3): 1.60 (d, 3H); 4,50 (bs, 2H, NH2); 5.10 (bs, 1H); 5.78 (bs, 1H); 6.08 (d, 1H); 6.25 (bs, 1H); 7.11 (t, 2H); 7.37 (m, 1H); 7.41 (m, 5H); 7.63 (dd, 2H); 8.22 (d, 1H). MS (m/z) EI: 425 (M+, 70); 410 (40).
Example 13
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine
Figure US06891039-20050510-C00055
The title compound is prepared from the sulfoxide (60 mg 0.16 mmol) in the above procedure and cyclopentylamine (0.8 ml) by heating to 120° C. for 1 h and purifying over RP18 (CH3CN/Water 70/30 to 10/90). The title compound is obtained as a yellow powder (30 mg 44%)
1H-NMR (400MHz; CDCl3): 1.47-2.15 (m, 8H); 4.20 (bs, 1H); 4.55 (s, 2H; NH2); 5.34 (bs, 1H); 6.15 (s, 1H, NH); 6.54 (d, 1); 7.12 (t, 2H); 7.68 (dd, 2H); 7.93 (d, 1H); 8.25 (d, 1H). MS (m/z) EI: 389 (M+, 100).
Example 14 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
a) 5-Nitro-6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine
Figure US06891039-20050510-C00056
6-Amino-2-chloro-5-nitropyridine (Acros, 3.66 g 21 mmol) and 1-ethoxycarbonylpiperazine (6.36 g 42 mmol) in isopropanol (85 ml) are refluxed for 3 h. The reaction mixture with a yellow precipitate is poured on water/Na2CO3 and extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as yellow crystals, which are purified by recrystallisation from tert.-butyl methyl ether (5.5 g 89%).
1H-NMR (400 MHz, CDCl3): 1.23 (t, 3H); 3.51 (m, 4H); 3.66 (m, 4H); 4.12 (q, 2H); 6.00 (d, 1H); 8.15 (d, 1H). MS (m/z) EI: 295 (M+, 60); 193 (50); 167 (100).
b) 5,6-Diamino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine
Figure US06891039-20050510-C00057
5-Nitro-6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (4.5 g 15.2 mmol) in EtOH (200 ml) is hydrogenated at 1 atm over 10% Pd/C (1.5 g), filtered after hydrogen uptake was complete (2.5 h), combined with 4-fluorobenzoic acid (2.13 g 15.2 mmol) in EtOH (50 ml), evaporated to dryness and used without further purification in the following step.
c) 2-(4-Fluorophenyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00058
The mixture of 5,6-Diamino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine from the previous hydrogenation (4.5 g, 15.2 mmol) and 4-fluorobenzoic acid (2.13 g 15.2 mmol) is treated with polyphosphoric acid (76 g) at 150° C. for 1 h 15 min. The reaction mixture is poured on ice-water/Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as brownish crystals (1.6 g, 35%).
1H-NMR (400 MHz; DMSO): 2.73 (m, 4H); 3.43 (m, 4H); 6.78 (d, 1H); 7.35 (t, 2H); 7.80 (d, 1H); 8.18 (dd, 2H). MS (m/z) CI: 298 (MH+, 100); 278 (20).
d) 2-(4-Fluorophenyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00059
2-(4-Fluorophenyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine (1.57 g, 5.3 mmol) in THF (53 ml) is treated with (BOC)2O (1.27 g, 5.83 mmol) for 30 min. at room temperature, poured on water and extracted with ethyl acetate three times. The combined organic phases are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (acetone/hexanes 10/80 to 50/50) yields the title compound (1.6 g, 74.5%) as brownish crystals.
1H-NMR (400 MHz; CDCl3): 1.52 (s, 9H); 3.52-3.73 (bs, 8H); 6.71 (d, 1H); 7.18 (t, 2H); 7.93 (bs, 1H); 8.07 (bt, 2H), 10.70 (bs, 1H, NH). MS (m/z) EI: 397 (M+, 100); 341 (90); 241 (100).
e) 2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00060
KN(MS)2 (812 mg, 3.85 mmol) in toluene (3.85 ml) is added at 0° C. to a solution of 2-(4-Fluorophenyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (1.4 g, 3.5 mmol) in DMF (7 ml). After stirring at room temperature for 30 min., 4-iodo-2-methylthiopyrimidine (970 mg, 3.85 mmol)in toluene (3.85 ml) is added and the reaction stirred at room temperature for 1 h. Toluene is evaporated, the reaction mixture heated to 120° C. for 18 h, poured on water and extracted with ethyl acetate (containing 5% EtOH) three times. The combined organic phases are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (acetone/hexanes 20/80) renders the title compound (950 mg, 52%) as colorless foam.
1H-NMR (400 MHz; CDCl3): 1.51 (s, 9H); 2.55 (s, 3H); 3.61 (m, 4H); 3.69 (m, 4H); 6.55 (d, 1H); 6.77 (d, 1H); 7.15 (t, 2H); 7.65 (dd, 2H); 8.06 (d, 1H); 8.47 (d, 1H). The correct regiochemistry was demonstrated by ROESY. MS (m/z) ESI: 522 (MH+, 100).
f) 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00061
2-(4Fluorophenyl)-1-(2-methylthio-4pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl) imidazo[4,5-b]pyridine (106 mg, 0.2 mmol) is dissolved in CH2Cl2/HOAc 1:1 (10 ml), combined with mCPBA (113 mg 70%, 0.24 mmol) and stirred for 15 min. The reaction mixture is poured on water and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude sulfoxide (100 mg), which is dissolved in 1-(S)-phenylethylamine (0.2 ml) and heated to 120° C. for 1 h. Purification over SiO2 (acetone/hexanes 1:1) yielded the title compound as colorless foam (45 mg 35%)
1H-NMR (400 MHz; CDCl3): 1.51 (s, 9H); 1.62 (d, 3H); 3.58-3.67 (m, 8H); 5.10 (bs, 1H); 5.75 (bs, 1H); 6.08 (d, 1H); 6.45 (bs 1H, NH); 7.11 (t, 2H); 7.33-7.43 (m, 6H); 7.65 (dd, 2H); 8.22 (d, MS (m/z) ESI: 595 (MH+, 100).
g) 2-(4-Fluorophenyl)-1-(2-(-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00062
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (280 mg, 0.67 mmol) is dissolved in EtOH/HClconc 1/1 (9.4 ml) and stirred at room temperature for 30 min. The reaction mixture is poured on a saturated solution of Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (tert.-butyl methyl ether/MeOH/NH3conc 90/9/1) yields the title compound as a yellow foam (200 mg, 86%)
1H-NMR (400 MHz; CDCl3): 1.61 (d, 3H); 1.89 (bs, 1H); 3.06 (t, 4H); 3.62 (bt, 4H); 5.10 (bs, 1H), 5.75 (bs, 1H); 6.09 (d, 1H); 6.45 (bs, 1H); 7.05 (bs, 1H); 7.11 (t, 2H); 7.32-7.46 (m, 5H); 7.66 (dd, 2H); 8.21 (d, 1H). MS (m/z) ESI: 495 (MH+, 100).
The compounds of Examples 15-17 are similarly prepared:
Example 15 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00063
1H-NMR (400 MHz; DMSO-d6, 120° C.): 1.43-1.58 (m, 4H); 1.65-1.75 (m, 2H); 1.80-1.90 (m, 2H); 3.10 (t, 4H); 3.73 (t, 4H); 4.00-4.08 (m, 1H); 6.38 (d, 1H); 6.90 (d, 1H); 6.95 (bd, 1H, NH); 7.26 (t, 2H); 7.68 (dd, 2H); 7.96 (d, 1H); 8.34 (d, 1H). MS (m/z) ESI: 459.3 (MH+, 100).
Example 16 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00064
1H-NMR (400 MHz; CDCl3): 1.65-1.89 (m, 4H); 1.91-2.05 (m, 2H; 2.43 (bs, 1H); 3.06 (t, 4H); 3.67 (t, 4H); 4.40 (bs, 1H, NH); 5.50 (bd, 1H, NH); 6.17 (bd, 1H); 6.75 (d, 1H); 7.11 (t, 2H); 7.68 (dd, 2H); 7.97 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 445.3 (MH+, 100).
Example 17 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00065
1H-NMR (400 MHz; DMSO-d6): 0.47 (bs, 2H); 0.62 (bs, 2H); 2.33 (bs, 1H); 2.83 (bt, 4H); 3.47 (bt, 4H); 6.34 (bs, 1H); 6.92 (d, 1H, NH); 7.36 (t, 2H); 7.65 (dd, 2H); 7.85 (bd, 1H); 8.10 (bs, 1H); 8.36 (bd, 1H). MS (m/z) ESI: 431.2 (MH+, 100).
Example 18 2-(4-Fluorophenyl)-1-(2-(-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00066
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4methyl-1-piperazinyl) imidazo[4,5-b]pyridine (50 mg, 0.1 mmol) is dissolved in MeOH (2.5 ml). An aqueous 36%-solution of formaldehyde (15.8 ml, 0.2 mmol) is added and stirred for 30 min. NaBH, (7.5 mg, 0.2 mmol) is added and stirring continued for 30 min. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO (tert.-butyl methyl ether/MeOH/NH3conc 90/9/1) yields the title compound as a yellow powder (35 mg 68%)
1H-NMR (400 MHz; CDCl3): 1.61 (d, 3H); 2.40 (s, 3H); 2.60 (bt, 4H); 3.68 (bt, 4H); 5.12 (m, 1H); 5.76 (bs, 1H, NH); 6.08 (d, 1H); 6.48 (bs 1H); 7.10 (t, 2H); 7.35-7.46 (1,6H); 7.66 (dd, 2H); 8.21 (d, 1H). MS (m/z) ESI: 509 (MH+, 100).
The compounds of Examples 19-21 are similarly prepared:
Example 19 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00067
1H-NMR (400 MHz; DMSO-d6): 1.45-1.58 (m, 2H); 1.61-1.83 (m, 4H); 1.97-2.13 (m, 2H); 2.38 (s, 3H); 2.59 (t, 4H); 3.71 (t, 4H); 4.10-4.31 (m, 1H); 5.33 (bd, 1H, NH); 6.16 (bs, 1H); 6.75 (d, 1H); 7.11 (t, 2H); 7.68 (dd, 2H); 7.97 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 473.3 (MH+, 100).
Example 20 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00068
1H-NMR (400 MHz; DMSO-d6): 1.45-2.12 (m, 6H); 2.20 (m, 1H); 2.25 (s, 3H); 2.45 (bt, 4H); 3.55 (bt, 4H); 6.95 (bs, 1H); 7.32 (t, 2H); 7.62 (bs, 2H); 7.93 (bd, 2H); 8.33 (bs, 1H). MS (m/z) ESI: 459.3 (MH+, 100).
Example 21 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00069
1H-NMR (400 MHz; CDCl3): 0.64 (m, 2H); 0.88 (m, 2H); 2.38 (s, 3H); 2.58 (t, 4H); 2.82 (bs, 1H); 3.72 (t, 4H); 5.58 (s, 1H, NH); 6.19 (d, 1H); 6.74 (d, 1H); 7.13 (t, 2H); 7.71 (dd, 2H); 8.12 (bs, 1H); 8.28 (bs, 1H). MS (m/z) ESI: 445 (MH+, 100).
Example 22 2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00070
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo [4,5-b]pyridine (60 mg, 0.12 mmol) and isobutyleneoxide (43.5 ml (0.6 mmol) in EtOH (6 ml) are heated at 80° C. for 3 h. The reaction mixture is evaporated and purified by SiO2 chromatography (tert.-butyl methyl ether/MeOH/NH3conc. 97/2.7/0.3) to yield the title compound as a yellow foam (40 mg 60%).
1H-NMR (400 MHz; DMSO, 120° C.): 1.18 (s, 6H); 1.48 (d, 3H); 2.43 (s, 2H); 2.72 (dd, 4H); 3.58 (dd, 4H); 5.10 (m, 1H); 6.32 (d, 1H); 6.73 (d, 1H); 7.21 (t, 2H); 7.28-7.38 (m, 5H); 7.43 (bd, 1H, NH); 7.62 (dd, 2H); 7.65 (d, 1H); 8.32 (d, 1H). MS (m/z) ESI: 567 (MH+, 100).
The compounds of Examples 23-25 are similarly prepared:
Example 23 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00071
1H-NMR (400 MHz; DMSO): 1.24 (s, 6H); 1.52 (bs, 2H); 1.67 (bs, 2H); 1.79 (bs, 2H); 2.08 (bs, 2H); 2.42 (s, 2H); 2.82 (bt, 4H); 3.20 (bs, 1H, OH); 3.70 (bt, 4H); 4.22 (bs, 1H); 5.35 (bd, 1H, NH); 6.17 (bs, 1H); 6.74 (d, 1H); 7.12 (t, 2H); 7.70 (dd, 2H); 7.97 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 531.3 (MH+, 100).
Example 24 2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00072
1H-NMR (400 MHz; DMSO): 1.25 (s, 6H); 1.56-2.03 (m, 6H); 2.43 (s, 2H); 2.82 (t, 4H); 3.15 (bs, 1H, OH); 3.70 (t, 4H); 4.40 (bs, 1H, NH); 5.50 (bd, 1H, NH); 6.15 (bs, 1H); 6.74 (d, 1H); 7.12 (t, 2H); 7.69 (dd, 2H); 7.98 (d, 1H); 8.25 (d, 1H). MS (m/z) ESI: 517.4 (MH+, 35).
Example 25 2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00073
1H-NMR (400 MHz; DMSO): 0.64 (m, 2H); 0.88 (m, 2H); 1.25 (s, 6H); 2.42 (s, 2H); 2.83 (m, 5H); 3.17 (s, 1H, OH); 3.70 (bt, 4H); 5.57 (s, 1H, NH); 6.20 (d, 1H); 6.73 (d, 1H); 7.13 (t, 2H); 7.71 (dd, 2H); 8.12 (bs, 1H); 8.29 (bs, 1H). MS (m/z) ESI: 503.3 (MH+, 40).
Example 26 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-piperidinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00074
2-(4Fluorophenyl)-1-(2cyclopentylamino-pyrimidinyl)-5-(4-pyridinyl)imdazo[4,5-b]pyridine (example 7; 100 mg; 0.22 mmol) is dissolved in HOAc (120 ml) and hydrogenated over Pd/C (10%, 200 mg) in a Parr apparatus for 48 h at room temperature. The reaction mixture is filtered and evaporated to dryness delivering the title compound as yellow crystals, which are recrystallised from MeOH and gave the title compound as colorless crystals (70 mg; 65%).
1H-NMR (400 MHz; DMSO-d6, 120° C.): 1.49 (m, 4H); 1.68 (m, 2H); 1.83 (m, 2H); 2.10 (m, 4H); 3.05 (dt, 4H); 3.18 (m, 1H); 3.48 (m, 4H); 4.03 (m, 1H); 6.45 (d, 1H); 7.05 (bd, 1H, NH); 7.30 (m, 2H); 7.70 (m, 2H); 8.08 (d, 1H); 8.40 (d, 1H). MS (m/z) ESI: 458.3 (MH+; 100).
Example 27 2-(4-fluorophenyl)-1-(2-cyclopentylamino-4-pyridinyl)-5-(1-methyl-4-piperidinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00075
The title compound is prepared in analogy to Example 18.
MS (m/z) ESI: 472.4 (MH+, 100).
Example 28 2-(4-Fluorphenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-(2-hydroxy-2-methyl)propyl-4-piperidinyl)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00076
The title compound is prepared in analogy to Example 22.
1H-NMR (400 MHz; DMSO-d6, 120° C.): 1.21 (s, 6H); 1.43-1.83 (m, 8H); 1.95-2.18 (m, 5H); 2.41 (s, 2H); 2.56 (bt, 2H); 2.88 (bt, 1H); 3.08 (bd, 2H); 5.37 (bs, 1H, NH); 6.21 (bs, 1H); 7.13 (t, 2H); 7.21 (d, 1H); 7.72 (dd, 2H); 8.06 (d, 1H); 8.28 (d, 1H).
MS (m/z) ESI: 530 (MH+, 100)
Example 29 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(benzylamino)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00077
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(chloro)imidazo[4,5-b]pyridine (100 mg; 0.25 mmol), R-(+)-BINAP (10 mg; 0.016 mmol), Pd2(dba)3 (22 mg; 0.024 mmol) are suspended in xylene (16 ml), benzylamine (0.53 ml; 4.9 mmol) is added, followed by NaOtBu (47 mg; 0.49 mmol) and heated to 160° C. for 10 min. under argon. The reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times. The combined organic phases are washed with 2N Na2CO3, dried over Na2SO4 and evaporated to dryness. Purification via SiO2 chromatography (TBME/hexane 6:4 to 10:0) and recrystalisation from TBME yields the title compound as colorless crystals (50 mg. 50%).
1H-NMR (400 MHz; CDCl3): 1.45-1.85 (m, 6H); 1.95-2.13 (m, 2H); 4.25 (bs, 1H); 4.72 (d, 1H); 4.86(bt, 1H, NH); 5.31 (bd, 1H, NH); 6.15 (, bs, 1H); 6.43 (d, 1H); 7.11 (t, 2H); 7.28 (m, 3H); 7.35 (t, 2H); 7.45 (d, 1H); 7.68 (dd, 2H); 7.89 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 480 (MH+, 100).
Example 30 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00078
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(chloro)imidazo[4,5-b]pyridine (100 mg; 0.25 mmol), R-(+)-BINAP (10 mg; 0.016 mmol), Pd2(dba)3 (22 mg; 0.024 mmol) are suspended in xylene (16 ml), morpholine (0.43 ml; 4.9 mmol) is added, followed by NaOtBu (47 mg; 0.49 mmol) and heated to 160° C. for 10 min. under argon. The reaction mixture is poured on water (100 ml) containing HOAc (2 ml) and extracted with TBME three times. The combined organic phases are washed with 2N Na2CO3, dried over Na2SO4 and evaporated to dryness. Purification via SiO2 chromatography (TBME/hexane 7:3 to 10:0) and recrystallisation from TBME yields the title compound as colorless crystals (22 mg: 19%).
1H-NMR (400 MHz; CDCl3): 1.47-1.84 (m, 6H); 1.97-2.17 (bs, 2H); 3.65 (m, 4H); 3.88 (m, 4H); 4.22 (bs, 1H); 5.33 (bs, 1H, NH); 6.16 (bs, 1H); 6.72 (d, 1H); 7.11 (t, 2H); 7.69 (dd, 2H); 8.00 (d, 1H); 8.25 (bd, 1H). MS (m/z) ESI: 460 (MH+, 100).
Example 31 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-fluorophenylamino)imidazo[4,5-b]pyridine
The title compound is prepared in analogy to Example 29
Figure US06891039-20050510-C00079
1H-NMR (400 MHz, CDCl3): 1.48-1.87 (m, 6H); 1.95-2.18 (m, 2H); 4.22 (s, 1H); 5.37 (bs, 1H, NH); 6.15 (bs, 1H); 6.72 (bs, 2H); 6.86 (d, 1H); 7.15 (t, 2H); 7.28 (m, 2H); 7.53 (d, 1H); 7.70 (dd, 2H); 8.03 (d, 1H); 8.27 (d, 1H). MS (m/z) ESI: 484 (MH+, 100).
Example 32 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyridyl-4-amino)imidazo[4,5-b]pyridine
The title compound is prepared in analogy to Example 29.
Figure US06891039-20050510-C00080
1H-NMR (400 MHz, CDCl3): 1.47-1.93 (m, 6H); 1.97-2.20 (m, 2H); 4.22 (m, 1H); 5.40 (d, 1H, NH); 6.17 (bs, 1H); 6.93 (d, 1H); 7.18 (m, 2H); 7.71 (m, 4H); 8.12 (d, 1H); 8.28 (d, 1H); 8.42 (d, 2H). MS (m/z) ESI: 467 (MH+, 100).
Example 33 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-ethoxycarbonylpiperidine-4-amino)imidazo[4,5-b]pyridine
The title compound is prepared in analogy to Example 29
Figure US06891039-20050510-C00081
1H-NMR (400 MHz, CDCl3): 1.31 (t, 3H); 1.38-1.85 (m, 10H); 1.93-2.13 (bs, 1H); 2.21 (bd, 2H); 3.05 (bt, 2H); 4.03-4.39 (m, 4H); 5.33 (bs, 1H, NH); 6.15 (bs, 1H); 6.40 (d, 1H); 7.11 (t, 2H); 7.66 (dd, 2H); 7.88 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 545 (MH+, 100).
Example 34 2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidine-4amino)imidazo[4,5-b]pyridine
Figure US06891039-20050510-C00082
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-ethoxycarbonylpiperidine-4-amino)imidazo[4,5-b]pyridine (58 mg; 0.1 mmol) is dissolved in CHCl3 (2 ml) and treated with trimethylsilyliodide (0.3 ml; 2.2 mmol) in a sealed vessel at 60° C. for 5 h. 6N HCl in isopropanol is added to the reaction mixture, which is then poured on 2N Na2CO3/2N NaOH and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield the crude title compound, which is purified via recrystallisation from THF/TBME (44 mg; 88%).
1H-NMR (400 MHz, CDCl3): 1.35-1.82 (m, 8H); 2.06 (bs, 2H); 2.22 (bd, 2H); 2.82 (bt, 2H); 3.15 (bd, 2H); 4.06-4.32 (m, 3H); 4.39 (d, 1H, NH); 5.32 (bd, 1H, NH); 6.14 (bs, 1H); 6.38 (d, 1H); 7.10 (t, 2H); 7.66 (dd, 2H); 7.87 (d, 1H); 8.23 (d, 1H). MS (m/z) ESI: 473.1 (MH+, 100).
The Agents of the Invention, as defined above, e.g., of formula I, II and V particularly as exemplified, in free or pharmaceutically acceptable acid addition salt form, exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy, in the treatment of diseases and conditions as hereinafter set forth.
In particular Agents of the Invention possess p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity. Thus the Agents of the Invention act to inhibit production of inflammatory cytokines, such as TNF-α and IL-1, and also to potentially block the effects of these cytokines on their target cells. These and other pharmacological activities of the Agents of the Invention as may be demonstrated in standard test methods for example as described below:
p38 MAP Kinase Assay
The substrate (GST-ATF-2; a fusion protein comprising amino acids 1-109 of ATF-2 and the GST protein obtained by expression in E. coli) is coated onto the wells of microtiter plates (50 μl/well; 1 μg/nd in PBS/0.02% Na azide) overnight at 4° C. The following day, the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide and are blocked with PBS/2% BSA/0.02% Na Azide for 1 h at 37° C. Plates are washed again 4 times with PBS/0.5% Tween 20/0.02% Na azide. The kinase cascade reaction is then started by adding the following reactants in 10 μl aliquots to a final reaction volume of 50 μl.
  • 1. Agents of the Invention titrated from 10 to 0.001 μM in 10-fold dilutions or solvent (DMSO) or H2O.
  • 2. Kinase buffer (5×); pH 7.4; 125 mM Hepes (Stock at 1M; Gibco #15630-056), 125 mM β-glycerophosphate (Sigma #G-6251):125 mM MgCl2 (Merck #5833); 0.5 mM Sodium orthovanadate (Sigma #5-6508), 10 mM DTT (Boehringer Mannheim #708992). The (5×) kinase buffer must be prepared fresh the day of the assay from 5× stock solutions kept at RT. DTT is kept at −20° C. and is added as the last reagent.
  • 3. His-p38 MAP kinase (10 ng/well; Novartis—a fusion protein comprising full length murine p38 MAP kinase and a His tag, obtained by expression in E. coli)
  • 4. cold ATP (final concentration 120 μM; Sigma #A-9187)
  • 5. Water
    After 1 h at 37° C. the kinase reaction is terminated by washing the plates four times as previously described. Phosphorylated GST-ATF-2 is then detected by adding:
  • 1. the PhosphoPlus ATF-2 (Thr71) Antibody (50 μl/well; 1/1000 final dilution in PBS/2% BSA/0.02% Na Azide; New England Biolabs #9221L) for 90 min at RT.
  • 2. Biotin labelled goat-anti-rabbit IgG (50 μl/well; 1/3000 final dilution in PBS/2% BSA/0.02% Na Azide; Sigma #B-9642) for 90 min at RT.
  • 3. Streptavidin-alkaline phosphatase (50 μl/well; 1/5000 dilution in PBS/2% BSA/0.02% Na Azide; Jackson Immunoresearch #016-050-084) for 30 min at RT.
  • 4. Substrate (100 μl/we11; Sigma 104 Phosphatase substrate tablets, 5 mg/tablet; #104-105; 1 mg/ml in substrate buffer, Diethanolamine (97 ml/l; Merck #803116)+MgCl2.6H2O (100 Mg/l; Merck #5833)+Na Azide (0.2 μl)+HCl 1M to pH 9.8) 30 min at RT.
    After step 1,2 and 3 the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide. After step 4, the plates are read in a Bio-Rad microplate reader in a dual wavelength mode (measurement filter 405 nm and reference filter 490 nm). The background value (without ATP) is subtracted and IC50 values are calculated using the Origin computer program (4 parameter logistic function).
Agents of the Invention typically have IC50s for p38 MAP kinase inhibition in the range from about 100 nM to about 5 nM or less when tested in the above assay.
Assay for Inhibition of TNFα Release from hPBMCs
Human peripheral blood mononuclear cells (hPBMCs) are prepared from the peripheral blood of healthy volunteers using ficoll-hypaque density separation according to the method of Hansell et al., J. Imm. Methods (1991) 145: 105. and used at a concentration of 105 cells/well in RPMI 1640 plus 10% FCS. Cells are incubated with serial dilutions of the test compounds for 30 minutes at 37° C. prior to the addition of IFNg (100 U/ml) and LPS (5 mg/ml) and subsequently further incubated for three hours. Incubation is terminate by centrifugation at 1400 RPM for 10 min. TNF-α in the supernatant is measured using a commercial ELISA (Innotest hTNFa, available from Innogenetics N.V., Zwijnaarde, Belgium). Agents of the Invention are tested at concentrations of from 0 to 10 MM. Exemplified Agents of the Ivention typically suppress TNF release in this assay with an IC50 of from about ? nM to about ? nM or less when tested in this assay.
Assay for Inhibition of TNFα Production in LPS Stimulated Mice
Injection of lipopolysaccharide (LPS) induces a rapid release of soluble tumour necrosis factor (TNF-α) into the periphery. This model is be used to analyse prospective blockers of TNF release in vivo.
LPS (20 mg/kg) is injected i.v. into OF1 mice (female, 8 week old). One (1) hour later blood is withdrawn from the animals and TNF levels are analysed in the plasma by an EUSA method using an antibody to TNF-α Using 20 mg/kg of LPS levels of up to 15 ng of TNF-α/ml plasma are usually induced. Compounds to be evaluated are given either orally or s.c. 1 to 4 hours prior to the LPS injection. Inhibition of LPS-induced TNF-release is taken as the readout.
Agents of the Invention typically inhibit TNF production to the extent of up to about 50% or more in the above assay when administered at 10 mg/kg p.o.
As indicated in the above assays Agents of the Invention are potent inhibitors of TNF-α release. Accordingly, the Novel Compounds have pharmaceutical utility as follows:
Agents of the Invention are useful for the prophylaxis and treatment of diseases or pathological conditions mediated by cytokines such as TNFα and IL-1, e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection, e.g. a for the treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants and for the prevention of graft-versus-host disease, such as following bone marrow transplants.
Agents of the Invention are particularly useful for the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific auto-immune diseases for which Agents of the Invention may be employed include autoimmune haematological disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or mini change nephropathy).
Agents of the Invention are also useful for the treatment, prevention, or amelioration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.
Agents of the Invention are useful for treating undesirable acute and hyperacute inflammatory reactions which are mediated by TNF, especially by TNFα, e.g., acute infections, for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especially AIDS-related cachexia, e.g., associated with or consequential to HIV infection.
Agents of the Invention are also useful for the treatment of neurodegenerative diseases, such as Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis including demyelation and oligiodendrocyte loss in multiple sclerosis and inflammatory nervous system diseases, such as neuroinflammatory and stroke.
Agents of the Invention are particularly useful for treating diseases of bone metabolism including osteoarthritis, osteoporosis and other inflammatory arthritides.
For the above indications the appropriate dosage will, of course, vary depending, for example, on the particular Agent of the Invention employed, the subject to be treated, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are obtained at daily dosages of from about 1 to about 10 mg/kg/day p.o. In larger mammals, for example humans, an indicated daily dosage is in the range of from about 50 to about 750 mg of an Agent of the Invention administered orally once or, more suitably, in divided dosages two to four times/day.
The Agents of the Invention may be administered by any conventional route, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions. Normally for systemic administration oral dosage forms are preferred, although for some indications the Agents of the Invention may also be administered topically or dermally, e.g. in the form of a dermal cream or gel or like preparation or, for the purposes of application to the eye, in the form of an ocular cream, gel or eye-drop preparation; or may be administered by inhalation, e.g., for treating asthma Suitable unit dosage forms for oral administration comprise e.g. from 25 to 250 mg of Agent of the Invention per unit dosage.
In accordance with the foregoing the present invention also provides in a further series of embodiments:
A. A method of inhibiting production of soluble TNF, especially TNFα, or of reducing inflammation in a subject (i.e., a mammal, especially a human) in need of such treatment which method comprises administering to said subject an effective amount of an Agent of the Invention, or a method of treating any of the above mentioned conditions, particularly a method of treating an inflammatory or autoimmune disease or condition, e.g. rheumatoid arthritis, or alleviating one or more symptoms of any of the above mentioned conditions.
B. An Agent of the Invention for use as a pharmaceutical, e.g. for use as an immunosuppressant or antiinflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
C. A pharmaceutical composition comprising an Agent of the Invention in association with a pharmaceutically acceptable diluent or carrier, e.g., for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
D. Use of an Agent of the Invention in the manufacture of a medicament for use as an immunosuppressant or anti-inflammatory agent or for use in the prevention, amelioration or treatment of any disease or condition as described above, e.g., an autoimmune of inflammatory disease or condition.

Claims (4)

1. A compound according to formula V in free or pharmaceutically acceptable salt form
Figure US06891039-20050510-C00083
wherein
R11 is pyrimidyl;
X is —NR8—Y—, —O— or —S—,
where R6 is H, C1-C4alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and —Y— is C1-C4alkylene or a direct bond;
R12 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
halo,
CF3,
cyano,
amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued,
carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkenoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester, optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5cycloalkyl-substituted-carbonyl or -thiocarbonyl
optionally halo-substituted-C1-C4alkoxy, C2-C4alkenoxy, C2-C4alkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
optionally halo substituted C1-C4 alkyl,
oxycarbonyl or optionally N—C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof),
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-N—C1-C4 alkyl substituted,
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally N—C1-C4alkyl-substituted amino-carbonyl or -thiocarbonyl,
optionally N—C1-C4alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by optionally mono- or di-N—C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted, or
sulphinyl or sulphonyl optionally substituted by optionally halo-substituted-C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
optionally mono- or di-N—C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substitued;
R13 is H, amino, C1-C10alkyl, C3-C10cycloalkyl, C3-C18heterocycloalkyl, C6-C18aryl, or C3-C18heteroaryl all optionally substituted by up to 4 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C6-C18aryl, C3-C18heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl C3-C18heterocycloalkyl or optionally mono- or di-N—C1-C4alkyl substituted amino all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy or C1-C4alkoxycarbonyl; and
R14 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.
2. A compound according to claim 1 of formula V′ in free or pharmaceutically acceptable salt form
Figure US06891039-20050510-C00084
wherein,
R14′ is phenyl or C3-C7cycloalkyl each of which is optionally mono-substituted by halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy, trihalomethyl optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
R10 is halogen, CF3, C1-C4alkyl or C1-C4alkoxy;
R13′ is pyridyl, pyrimidyl, piperazinyl, piperidinyl, NR9R10, —CH2OH, CH2NR15R16, CH2CHR15R16, or Het-C1-C4alkyl-,
wherein
R9 and R10 are separately selected from H, C1-C4alkyl, C6-C18aryl, C3-C18 heteroaryl, C6-C18arylC1-C4alkyl, C3-C18heteroarylC1-C4alkyl all of which are optionally substituted by halo, hydroxy, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl;
Het is a N-heterocyclyl containing from 5 to 7 ring atoms where said ring atoms optionally containing a further heteroatom selected from the group consisting of O, S, and N;
R15 and R16 are independently selected from H and C1-C4 alkyl;
X″ is —NH—Y′—, —O— or —S—, where Y′ is —CH2—, —CH2—CH2—, —CH9(CH3)— or a direct bond.
3. A compound according to claim 1 selected from:
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(N,N-diethylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino-N-2-ethyl)ibidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(isopropylamino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyrrolidino-N-2-ethyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-pyridyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-pyridyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(4-NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4pyrimidinyl)-5-(4NH-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-(methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-(4-methyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-(S)-phenylethyl)amino-4-pyrimidinyl)-5-(4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-((4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4Fluorophenyl)-1-(2-cyclobutylamino-4-pyrimidinyl)-5-((4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopropylamino-4-pyrimidinyl)-5-((4-(2-hydroxy-2-methyl)propyl-1-piperazinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(4-piperidinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-methyl-4-piperidinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-(2-hydroxy-2-methyl)propyl-4-piperidinyl)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(benzylamino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(morpholino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(3-fluorophenyl amino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(pyridyl-4-amino)imidazo[4,5-b]pyridine;
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(1-ethoxycarbonyl piperidine-4-amino)imidazo[4,5-b]pyridine, and
2-(4-Fluorophenyl)-1-(2-cyclopentylamino-4-pyrimidinyl)-5-(piperidine-4-amino)imidazo[4,5b]pyridine.
4. A process for the production of
a compound of formula V″ in free or pharmaceutically acceptable salt form
Figure US06891039-20050510-C00085
wherein
R11 is pyrimidyl;
R12 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from
halo,
CF3,
cyano,
amido or thioamido which is optionally mono- or di-N-substituted by C1-C4alkyl or the N atom of which forms a 5-7 membered heterocyclic ring optionally containing an additional hetero atom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted,
carboxylate or thiocarboxylate optionally in the form of an optionally halo-substituted C1-C10alkoxy, C2-C10alkenoxy, C2-C10alkynoxy, C3-C7cyclalkoxy, C5-C7cycloalkoxy, aryloxy, arylalkoxy, heteroaryloxy or heteroarylalkoxy ester, optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally C1-C4alkyl- or C3-C5cycloalkyl-substituted-carbonyl or -thiocarbonyl,
optionally halo-substituted-C1-C4alkoxy, C2-Calkenoxy, C2-Calkynoxy, C3-C5cycloalkoxy or C3-C5cyclothioalkoxy,
optionally halo substituted C1-C4 alkyl,
oxycarbonyl or optionally N—C1-C4alkyl-substituted aminocarbonyl both of which are optionally C1-C4alkyl or C3-C5cycloalkyl substituted (including thiocarbonyl analogues thereof).
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkylamine which is optionally mono- or di-N—C1-C4 alkyl substituted,
optionally mono- or di-C1-C4alkyl-substituted-C0-C1alkyl optionally N—C1-C4alkyl-substituted amino-carbonyl or -thiocarbonyl,
optionally N—C1-C4 alkyl-substituted amino-sulphinyl or -sulphonyl optionally substituted by optionally mono- or -di-N—C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic ring of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4 alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted, or
sulphinyl or sulphonyl optionally substituted by optionally halo-substituted-C1-C4-alkyl, C2-C4 alkenyl, C2-C4 alkynyl,
optionally mono- or di-N—C1-C4alkyl-substituted amino,
a nitrogen atom which form a heterocyclic rind of 5 to 7 members optionally containing an additional heteroatom selected from O, S or N which N is optionally C1-C4alkyl C1-C4alkylcarbonyl or C1-C4alkylthiocarbonyl substituted;
R14 is C1-C10alkyl, C6-C18aryl, C3-C18heteroaryl, or C3-C12cycloalkyl optionally substituted by up to 3 substituents separately selected from C1-C4alkyl, halogen, halo-substitued-C1-C4alkyl, hydroxyl, C1-C4alkoxy, C1-C4alkylthio, optionally mono- or di-N—C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N;
X is —NR6—Y—, —O— or —S—, wherein R6 is H, C1-C4alkyl, C6-C18aryl, C3-C18heteroaryl, C7-C19aralkyl or C4-C19heteroaralkyl, and —Y— is C1-C4alkylene or a direct bond;
R13″ is —CH2—CH2NR15R16 or —CH2—CH2-Het wherein
R15 and R16 are independently selected from H and C1-C4alkyl; and
Het is a N-heterocyclyl containing from 5 to 7 ring atoms where said ring atoms optionally containing a further heteroatom selected from the group consisting of O, S, and N;
comprising reacting a corresponding vinyl precursor of formula VI
Figure US06891039-20050510-C00086
 wherein R11, R12, R14 and X are as previously defined with the corresponding amine of formula HNR15R16, or N-heterocycloalkyl ring compound;
(ii) a compound of formula V according to claim 1
Figure US06891039-20050510-C00087
 wherein R13 is aryl or heteroaryl comprising arylation or heteroarylation of a compound of formula VII
Figure US06891039-20050510-C00088
 wherein R11, R12, R14 and X are as previously defined in claim 1;
(iii) a compound of formula V according to claim 1 wherein R13 is —N-heterocycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, —NH—(C1-C4alkyl)-heterocycloalkyl, —NH—(C1-C4alkyl)-aryl, —NH—(C1-C4alkyl)-heteroaryl, or —NH—(C1-C4alkyl)-heterocycloalkyl comprising coupling a corresponding chloroprecursor compound of formula VII, as defined above, with the corresponding N-heterocycloalkyl compound or amine;
(iv) a compound of formula V according to claim 1 in which R13 is —NH2, comprising reacting the corresponding methyl sulphinyl compound of formula VIII′
Figure US06891039-20050510-C00089
 wherein R11, and R12 are as previously defined in claim 1;
(v) a compound of formula V according to claim 1 in which R13 is piperazinyl, comprising reacting a corresponding methylsulphinyl compound of formula VIII′
Figure US06891039-20050510-C00090
 wherein R11, and R12 are as previously defined in claim 1 and P is an N protecting group, with the corresponding amine of formula R14—NH2; and
(vi) recovering the resultant compounds of formula (V″) or (V) in free or pharmaceutically acceptable salt form.
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